rs114115159

Positions:

• chr11-6604336-A-G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_004517.4(ILK):​c.65A>G​(p.Asn22Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00117 in 1,611,672 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00081 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (3 hom.)
• Consequence: ILK NM_004517.4 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts U:1 B:8
• Conservation: PhyloP100: 8.44

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.019182503).
• BP6: Variant 11-6604336-A-G is Benign according to our data. Variant chr11-6604336-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 201788.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-6604336-A-G is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd4 at 123 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ILK	NM_004517.4	c.65A>G	p.Asn22Ser	missense_variant	2/13	ENST00000299421.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ILK	ENST00000299421.9	c.65A>G	p.Asn22Ser	missense_variant	2/13	1	NM_004517.4	P1
	ENST00000527191.1	n.85T>C		non_coding_transcript_exon_variant	1/2	3

Frequencies

GnomAD3 genomes AF: 0.000808 AC: 123 AN: 152216 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000753

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00137

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00115 AC: 281 AN: 243902 Hom.: 0 AF XY: 0.00117 AC XY: 155 AN XY: 132336

Gnomad AFR exome AF: 0.000389

Gnomad AMR exome AF: 0.0000878

Gnomad ASJ exome AF: 0.000303

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00103

Gnomad NFE exome AF: 0.00220

Gnomad OTH exome AF: 0.00101

GnomAD4 exome AF: 0.00121 AC: 1766 AN: 1459338 Hom.: 3 Cov.: 30 AF XY: 0.00119 AC XY: 867 AN XY: 725732

Gnomad4 AFR exome AF: 0.000179

Gnomad4 AMR exome AF: 0.0000449

Gnomad4 ASJ exome AF: 0.000192

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00162

Gnomad4 NFE exome AF: 0.00145

Gnomad4 OTH exome AF: 0.000863

GnomAD4 genome AF: 0.000807 AC: 123 AN: 152334 Hom.: 1 Cov.: 32 AF XY: 0.000698 AC XY: 52 AN XY: 74506

Gnomad4 AFR AF: 0.000313

Gnomad4 AMR AF: 0.000457

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000753

Gnomad4 NFE AF: 0.00137

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00125 Hom.: 0

Bravo AF: 0.000759

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.000682 AC: 3

ESP6500EA AF: 0.000698 AC: 6

ExAC AF: 0.00138 AC: 168

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:1 Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 13, 2021	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not specified Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 18, 2015	p.Asn22Ser in exon 1 of ILK: This variant is not expected to have clinical signi ficance because it has been identified in 0.3% (151/47102) of European chromosom es by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; db SNP rs114115159). -
Uncertain significance, no assertion criteria provided	clinical testing	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Jun 12, 2015	Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. ILK p.Asn22Ser Given lack of case data and the presence in the general population, we consider this variant a variant of uncertain significance. The variant has not been reported in association with disease. In silico analysis is inconsistent. The variant was reported online in 158 of 42181 individuals in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), which currently includes variant calls on ~64,000 individuals of European, African, Latino and Asian descent (as of June 11th, 2015). The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. -

Cardiomyopathy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego

Sep 08, 2017

- -

Primary familial hypertrophic cardiomyopathy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 22, 2024

- -

ILK-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 16, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.38
CADD	Uncertain	26
DANN	Uncertain	0.98
DEOGEN2	Benign	0.13	T;T;T;.;T;.;.
Eigen	Uncertain	0.20
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Uncertain	0.79	D
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.019	T;T;T;T;T;T;T
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	0.90	L;.;L;L;L;.;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-1.4	N;.;N;N;N;.;.
REVEL	Benign	0.18
Sift	Benign	0.27	T;.;T;T;T;.;.
Sift4G	Benign	0.14	T;T;T;T;T;T;T
Polyphen		0.90	P;.;P;.;P;.;.
Vest4		0.62
MVP		0.80
MPC		0.36
ClinPred		0.081	T
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.61
gMVP		0.38

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs114115159; hg19: chr11-6625566;