6-53009535-G-C

Variant names:

• chr6-53009535-G-C
• rs141663565
• NM_014920.5:c.1525C>G

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.1525C>G​(p.Pro509Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,459,196 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P509S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CILK1 NM_014920.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.51
• 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=0.07366139).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CILK1	NM_014920.5	c.1525C>G	p.Pro509Ala	missense_variant	Exon 12 of 14	ENST00000676107.1	NP_055735.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CILK1	ENST00000676107.1	c.1525C>G	p.Pro509Ala	missense_variant	Exon 12 of 14		NM_014920.5	ENSP00000501692.1
CILK1	ENST00000350082.10	c.1546C>G	p.Pro516Ala	missense_variant	Exon 12 of 14	1		ENSP00000263043.8
CILK1	ENST00000356971.3	c.1525C>G	p.Pro509Ala	missense_variant	Exon 13 of 15	2		ENSP00000349458.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1459196 Hom.: 0 Cov.: 29 AF XY: 0.00000138 AC XY: 1 AN XY: 726096

African (AFR) AF: 0.00 AC: 0 AN: 33414

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39684

South Asian (SAS) AF: 0.00 AC: 0 AN: 86198

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1109556

Other (OTH) AF: 0.00 AC: 0 AN: 60318

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 21, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1525C>G (p.P509A) alteration is located in exon 13 (coding exon 11) of the ICK gene. This alteration results from a C to G substitution at nucleotide position 1525, causing the proline (P) at amino acid position 509 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.060
BayesDel_addAF	Benign	-0.067	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	15
DANN	Benign	0.87
DEOGEN2	Benign	0.012	T;T
Eigen	Benign	-0.16
Eigen_PC	Benign	0.059
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.43	.;T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.074	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.81	L;L
PhyloP100		2.5
PrimateAI	Benign	0.33	T
PROVEAN	Benign	0.46	N;N
REVEL	Benign	0.097
Sift	Benign	0.39	T;T
Sift4G	Benign	0.92	T;T
Polyphen		0.0	B;B
Vest4		0.17
MutPred		0.19		Loss of stability (P = 0.008);Loss of stability (P = 0.008);
MVP		0.69
MPC		0.24
ClinPred		0.54	D
GERP RS		5.6
Varity_R		0.019
gMVP		0.11
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

dbSNP: rs141663565; hg19: chr6-52874333;