Mutagenetix > Incidental Mutation

Incidental Mutation 'H8930:Cilk1'

541

Institutional Source

Beutler Lab

Gene Symbol

Cilk1

Ensembl Gene

ENSMUSG00000009828

Gene Name

ciliogenesis associated kinase 1

Synonyms

2210420N10Rik, Ick

Accession Numbers

Essential gene?

Probably essential (E-score: 0.833) question?

Stock #

H8930 (G3) of strain frazz

Quality Score

Status

Validated

Chromosome

Chromosomal Location

78016474-78079389 bp(+) (GRCm39)

Type of Mutation

missense

DNA Base Change (assembly)

T to A at 78057901 bp (GRCm39)

Zygosity

Heterozygous

Amino Acid Change

Isoleucine to Asparagine at position 150 (I150N)

Ref Sequence

ENSEMBL: ENSMUSP00000112961 (fasta)

Gene Model

predicted gene model for transcript(s): [ENSMUST00000044551] [ENSMUST00000117330] [ENSMUST00000118869]

AlphaFold

Q9JKV2

Predicted Effect

possibly damaging
Transcript: ENSMUST00000044551
AA Change: I150N

PolyPhen 2 Score 0.923 (Sensitivity: 0.81; Specificity: 0.94)

SMART Domains

Protein: ENSMUSP00000048234
Gene: ENSMUSG00000009828
AA Change: I150N

Domain	Start	End	E-Value	Type
S_TKc	4	284	2.7e-102	SMART
low complexity region	310	327	N/A	INTRINSIC
low complexity region	331	344	N/A	INTRINSIC
low complexity region	413	422	N/A	INTRINSIC
low complexity region	457	471	N/A	INTRINSIC
low complexity region	513	551	N/A	INTRINSIC

Predicted Effect

possibly damaging
Transcript: ENSMUST00000117330
AA Change: I150N

PolyPhen 2 Score 0.854 (Sensitivity: 0.83; Specificity: 0.93)

SMART Domains

Protein: ENSMUSP00000113655
Gene: ENSMUSG00000009828
AA Change: I150N

Domain	Start	End	E-Value	Type
S_TKc	4	284	2.7e-102	SMART
low complexity region	310	327	N/A	INTRINSIC
low complexity region	331	344	N/A	INTRINSIC
low complexity region	413	422	N/A	INTRINSIC
low complexity region	457	471	N/A	INTRINSIC
low complexity region	513	539	N/A	INTRINSIC

Predicted Effect

possibly damaging
Transcript: ENSMUST00000118869
AA Change: I150N

PolyPhen 2 Score 0.923 (Sensitivity: 0.81; Specificity: 0.94)

SMART Domains

Protein: ENSMUSP00000112961
Gene: ENSMUSG00000009828
AA Change: I150N

Domain	Start	End	E-Value	Type
S_TKc	4	284	2.7e-102	SMART
low complexity region	310	327	N/A	INTRINSIC
low complexity region	331	344	N/A	INTRINSIC
low complexity region	413	422	N/A	INTRINSIC
low complexity region	457	471	N/A	INTRINSIC
low complexity region	513	551	N/A	INTRINSIC

Predicted Effect

noncoding transcript
Transcript: ENSMUST00000142402

Meta Mutation Damage Score

0.1795

Coding Region Coverage

1x: 77.1%
3x: 50.6%

Het Detection Efficiency

25.5%

Validation Efficiency

74% (89/120)

MGI Phenotype

FUNCTION: [Summary is not available for the mouse gene. This summary is for the human ortholog.] Eukaryotic protein kinases are enzymes that belong to a very extensive family of proteins which share a conserved catalytic core common with both serine/threonine and tyrosine protein kinases. This gene encodes an intestinal serine/threonine kinase harboring a dual phosphorylation site found in mitogen-activating protein (MAP) kinases. The protein localizes to the intestinal crypt region and is thought to be important in intestinal epithelial cell proliferation and differentiation. Alternative splicing has been observed at this locus and two variants, encoding the same isoform, have been identified. [provided by RefSeq, Jul 2008]
PHENOTYPE: Mice homozygous for a null allele exhibit abnormal primary cilium morphology and Shh signaling during limb digit patterning, peripheral edema, cleft palate, hydrocephalus, polydactyly, delayed skeletal development, and embryonic lethality at late stages of gestation. [provided by MGI curators]

Allele List at MGI

All alleles(29) : Targeted, other(1) Gene trapped(28)

Other mutations in this stock

Total: 7 list
Gene	Ref	Var	Chr/Loc	Mutation	Predicted Effect	Zygosity
Cdc20b	A	T	13: 113,220,500 (GRCm39)	I460F	probably damaging	Homo
Ddx4	A	C	13: 112,750,367 (GRCm39)		probably null	Homo
Malt1	T	G	18: 65,595,886 (GRCm39)	Y442*	probably null	Het
Mtr	A	G	13: 12,250,346 (GRCm39)	S346P	probably damaging	Het
Nup155	T	C	15: 8,187,142 (GRCm39)	V1357A	possibly damaging	Het
Prl3c1	T	A	13: 27,384,689 (GRCm39)	L46*	probably null	Het
Spata1	A	T	3: 146,193,026 (GRCm39)	L155*	probably null	Homo

Other mutations in Cilk1

Allele	Source	Chr	Coord	Type	Predicted Effect	PPH Score
IGL00965:Cilk1	APN	9	78,071,821 (GRCm39)	missense	probably benign	0.00
IGL01679:Cilk1	APN	9	78,047,307 (GRCm39)	missense	possibly damaging	0.94
IGL02525:Cilk1	APN	9	78,067,675 (GRCm39)	missense	probably benign	0.37
IGL02719:Cilk1	APN	9	78,047,301 (GRCm39)	missense	probably damaging	0.99
BB001:Cilk1	UTSW	9	78,062,746 (GRCm39)	missense	probably damaging	1.00
BB011:Cilk1	UTSW	9	78,062,746 (GRCm39)	missense	probably damaging	1.00
R0471:Cilk1	UTSW	9	78,062,799 (GRCm39)	critical splice donor site	probably null
R1626:Cilk1	UTSW	9	78,057,919 (GRCm39)	missense	probably damaging	1.00
R1824:Cilk1	UTSW	9	78,065,144 (GRCm39)	missense	probably benign
R2186:Cilk1	UTSW	9	78,038,769 (GRCm39)	missense	probably benign	0.07
R2872:Cilk1	UTSW	9	78,047,382 (GRCm39)	splice site	probably null
R2872:Cilk1	UTSW	9	78,047,382 (GRCm39)	splice site	probably null
R4609:Cilk1	UTSW	9	78,075,071 (GRCm39)	utr 3 prime	probably benign
R4737:Cilk1	UTSW	9	78,057,936 (GRCm39)	missense	probably damaging	1.00
R4792:Cilk1	UTSW	9	78,060,975 (GRCm39)	missense	probably damaging	1.00
R5001:Cilk1	UTSW	9	78,038,801 (GRCm39)	missense	probably damaging	1.00
R5060:Cilk1	UTSW	9	78,060,978 (GRCm39)	missense	probably benign	0.01
R5093:Cilk1	UTSW	9	78,047,303 (GRCm39)	missense	probably benign	0.24
R5393:Cilk1	UTSW	9	78,067,997 (GRCm39)	missense	probably benign
R6199:Cilk1	UTSW	9	78,071,921 (GRCm39)	missense	probably benign	0.04
R6412:Cilk1	UTSW	9	78,047,258 (GRCm39)	missense	probably damaging	1.00
R7038:Cilk1	UTSW	9	78,016,484 (GRCm39)	unclassified	probably benign
R7468:Cilk1	UTSW	9	78,065,221 (GRCm39)	missense	probably benign	0.00
R7660:Cilk1	UTSW	9	78,074,902 (GRCm39)	missense	probably benign
R7661:Cilk1	UTSW	9	78,074,902 (GRCm39)	missense	probably benign
R7662:Cilk1	UTSW	9	78,074,902 (GRCm39)	missense	probably benign
R7666:Cilk1	UTSW	9	78,074,902 (GRCm39)	missense	probably benign
R7693:Cilk1	UTSW	9	78,065,008 (GRCm39)	missense	probably benign
R7783:Cilk1	UTSW	9	78,042,927 (GRCm39)	missense	probably damaging	0.97
R7787:Cilk1	UTSW	9	78,074,902 (GRCm39)	missense	probably benign
R7788:Cilk1	UTSW	9	78,074,902 (GRCm39)	missense	probably benign
R7924:Cilk1	UTSW	9	78,062,746 (GRCm39)	missense	probably damaging	1.00
R8317:Cilk1	UTSW	9	78,060,933 (GRCm39)	missense	probably damaging	0.98
R8861:Cilk1	UTSW	9	78,071,844 (GRCm39)	missense	probably benign	0.01
R9131:Cilk1	UTSW	9	78,074,230 (GRCm39)	missense	possibly damaging	0.89
R9749:Cilk1	UTSW	9	78,060,999 (GRCm39)	missense	probably damaging	0.99
R9782:Cilk1	UTSW	9	78,048,520 (GRCm39)	missense	probably damaging	0.99
X0067:Cilk1	UTSW	9	78,062,685 (GRCm39)	nonsense	probably null

Nature of Mutation

DNA sequencing using the SOLiD technique identified a T to A transversion at position 915 of the Ick transcript in exon 7 of 15 total exons. Multiple transcripts of the Ick gene are displayed on Ensembl and Vega. The mutated nucleotide causes an isoleucine to asparagine substitution at amino acid 150 of the encoded protein. The mutation has been confirmed by DNA sequencing using the Sanger method (Figure 1).

Protein Function and Prediction

The Ick gene encodes a 629 amino acid serine/threonine protein kinase that may play a role in cardiac development. The protein is highly expressed in intestines and lung, with lower levels present in heart, esophagus, stomach, small intestine and ovary. ICK is autophosophorylated on various serines and threonines, which may lead to enzyme activation (Uniprot Q9JKV2). The kinase contains a conserved catalytic kinase domain that consists of 12 subdomains, a conserved TDY dual phosphorylation motif in subdomain VIII, and a proline-rich SH3-binding domain. Mutation analysis on the human homologue showed that 4 highly conserved lysines near the N terminus were required for ATP binding and catalytic activity, and that dual phosphorylation at the TDY motif was required for catalytic activity. A homozgyous mutation in the human gene was found to cause endocrine-cerebroosteodysplasia (ECO; OMIM 612651). The phenotype was severe, involved several organ systems, and resulted in fetal or neonatal death.

The I150N change occurs in the kinase domain, and is predicted to be probably damaging by the PolyPhen program.

Posted On

2010-11-11