11-6604307-C-G

Variant names:

• chr11-6604307-C-G
• rs199789449
• NM_004517.4:c.36C>G

Variant summary

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

The NM_004517.4(ILK):​c.36C>G​(p.Asn12Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. N12S) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ILK NM_004517.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.410
• Publications: 1 publications found

Genes affected

ILK (HGNC:6040): (integrin linked kinase) This gene encodes a protein with a kinase-like domain and four ankyrin-like repeats. The encoded protein associates at the cell membrane with the cytoplasmic domain of beta integrins, where it regulates integrin-mediated signal transduction. Activity of this protein is important in the epithelial to mesenchymal transition, and over-expression of this gene is implicated in tumor growth and metastasis. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jun 2013]

ILK Gene-Disease associations (from GenCC):

• dilated cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ENSG00000254400 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004517.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ILK	NM_004517.4	MANE Select	c.36C>G	p.Asn12Lys	missense	Exon 2 of 13	NP_004508.1
	ILK	NM_001014794.3		c.36C>G	p.Asn12Lys	missense	Exon 2 of 13	NP_001014794.1
	ILK	NM_001014795.3		c.36C>G	p.Asn12Lys	missense	Exon 1 of 12	NP_001014795.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ILK	ENST00000299421.9	TSL:1 MANE Select	c.36C>G	p.Asn12Lys	missense	Exon 2 of 13	ENSP00000299421.4
	ILK	ENST00000396751.6	TSL:1	c.36C>G	p.Asn12Lys	missense	Exon 1 of 12	ENSP00000379975.2
	ILK	ENST00000420936.6	TSL:1	c.36C>G	p.Asn12Lys	missense	Exon 2 of 13	ENSP00000403487.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Primary familial hypertrophic cardiomyopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Benign	-0.00028	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.23	T
Eigen	Benign	-0.018
Eigen_PC	Benign	-0.10
FATHMM_MKL	Benign	0.46	N
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.15	D
MetaRNN	Uncertain	0.62	D
MetaSVM	Benign	-0.44	T
MutationAssessor	Benign	1.6	L
PhyloP100		0.41
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-3.3	D
REVEL	Uncertain	0.43
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.014	D
Polyphen		1.0	D
Vest4		0.83
MutPred		0.49		Gain of ubiquitination at N12 (P = 0.0408)
MVP		0.82
MPC		1.1
ClinPred		0.99	D
GERP RS		-1.1
PromoterAI		-0.022	Neutral
Varity_R		0.72
gMVP		0.79
Mutation Taster		=45/55	disease causing

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

dbSNP: rs199789449; hg19: chr11-6625537;