NM_014920.5:c.1789T>A

Variant names:

• chr6-53005259-A-T
• NM_014920.5:c.1789T>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_014920.5(CILK1):​c.1789T>A​(p.Phe597Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CILK1 NM_014920.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.80
• Publications: 0 publications found

Genes affected

CILK1 (HGNC:21219): (ciliogenesis associated kinase 1) 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]

CILK1 Gene-Disease associations (from GenCC):

• endocrine-cerebro-osteodysplasia syndrome

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp
• juvenile myoclonic epilepsy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08957493).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CILK1	NM_014920.5	c.1789T>A	p.Phe597Ile	missense_variant	Exon 14 of 14	ENST00000676107.1	NP_055735.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CILK1	ENST00000676107.1	c.1789T>A	p.Phe597Ile	missense_variant	Exon 14 of 14		NM_014920.5	ENSP00000501692.1
CILK1	ENST00000350082.10	c.1810T>A	p.Phe604Ile	missense_variant	Exon 14 of 14	1		ENSP00000263043.8
CILK1	ENST00000356971.3	c.1789T>A	p.Phe597Ile	missense_variant	Exon 15 of 15	2		ENSP00000349458.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 09, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: CILK1 c.1789T>A (p.Phe597Ile) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 251414 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1789T>A in individuals affected with CILK1-Related Disorders and no experimental evidence demonstrating its impact on protein function have been reported. No submitters have cited clinical-significance assessments for this variant to ClinVar. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.086	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	22
DANN	Benign	0.97
DEOGEN2	Benign	0.0068	T;T
Eigen	Benign	-0.13
Eigen_PC	Benign	0.054
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.70	.;T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.090	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.69	N;N
PhyloP100		2.8
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-0.30	N;N
REVEL	Benign	0.076
Sift	Benign	0.35	T;T
Sift4G	Benign	0.39	T;T
Polyphen		0.046	B;B
Vest4		0.25
MutPred		0.18		Loss of methylation at R595 (P = 0.0815);Loss of methylation at R595 (P = 0.0815);
MVP		0.67
MPC		0.35
ClinPred		0.37	T
GERP RS		5.0
Varity_R		0.088
gMVP		0.26
Mutation Taster		=89/11	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

hg19: chr6-52870057;