chr11-6608092-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP3BS2

The NM_004517.4(ILK):​c.136C>T​(p.Arg46Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000547 in 1,461,880 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

ILK
NM_004517.4 missense

Scores

6
5
8

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 4.60
Variant links:
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]
TAF10 (HGNC:11543): (TATA-box binding protein associated factor 10) Initiation of transcription by RNA polymerase II requires the activities of more than 70 polypeptides. The protein that coordinates these activities is transcription factor IID (TFIID), which binds to the core promoter to position the polymerase properly, serves as the scaffold for assembly of the remainder of the transcription complex, and acts as a channel for regulatory signals. TFIID is composed of the TATA-binding protein (TBP) and a group of evolutionarily conserved proteins known as TBP-associated factors or TAFs. TAFs may participate in basal transcription, serve as coactivators, function in promoter recognition or modify general transcription factors (GTFs) to facilitate complex assembly and transcription initiation. This gene encodes one of the small subunits of TFIID that is associated with a subset of TFIID complexes. Studies with human and mammalian cells have shown that this subunit is required for transcriptional activation by the estrogen receptor, for progression through the cell cycle, and may also be required for certain cellular differentiation programs. [provided by RefSeq, Jul 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PP3
MetaRNN computational evidence supports a deleterious effect, 0.777
BS2
High AC in GnomAdExome4 at 8 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ILKNM_004517.4 linkc.136C>T p.Arg46Cys missense_variant Exon 3 of 13 ENST00000299421.9 NP_004508.1 Q13418-1V9HWF0
TAF10NM_006284.4 linkc.*2830G>A 3_prime_UTR_variant Exon 5 of 5 ENST00000299424.9 NP_006275.1 Q12962

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ILKENST00000299421.9 linkc.136C>T p.Arg46Cys missense_variant Exon 3 of 13 1 NM_004517.4 ENSP00000299421.4 Q13418-1
TAF10ENST00000299424 linkc.*2830G>A 3_prime_UTR_variant Exon 5 of 5 1 NM_006284.4 ENSP00000299424.4 Q12962

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000398
AC:
1
AN:
251456
Hom.:
0
AF XY:
0.00000736
AC XY:
1
AN XY:
135906
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000289
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000547
AC:
8
AN:
1461880
Hom.:
0
Cov.:
31
AF XY:
0.00000550
AC XY:
4
AN XY:
727240
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000540
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
Alfa
AF:
0.0000658
Hom.:
0
Bravo
AF:
0.0000151

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Uncertain:1
Jul 24, 2023
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The p.R46C variant (also known as c.136C>T), located in coding exon 2 of the ILK gene, results from a C to T substitution at nucleotide position 136. The arginine at codon 46 is replaced by cysteine, an amino acid with highly dissimilar properties. This amino acid position is conserved. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Primary familial hypertrophic cardiomyopathy Uncertain:1
Oct 24, 2022
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant is present in population databases (no rsID available, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with ILK-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C65"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 46 of the ILK protein (p.Arg46Cys). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.77
BayesDel_addAF
Pathogenic
0.24
D
BayesDel_noAF
Pathogenic
0.19
CADD
Pathogenic
28
DANN
Uncertain
1.0
DEOGEN2
Benign
0.26
T;T;T;.;T;.
Eigen
Benign
0.18
Eigen_PC
Uncertain
0.35
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.96
.;D;.;D;D;D
M_CAP
Benign
0.046
D
MetaRNN
Pathogenic
0.78
D;D;D;D;D;D
MetaSVM
Benign
-0.75
T
MutationAssessor
Benign
1.7
L;.;L;L;L;.
PrimateAI
Pathogenic
0.86
D
PROVEAN
Uncertain
-3.0
D;.;D;D;D;.
REVEL
Uncertain
0.46
Sift
Benign
0.061
T;.;T;T;T;.
Sift4G
Benign
0.16
T;T;T;T;T;T
Polyphen
0.20
B;.;B;.;B;.
Vest4
0.90
MVP
0.77
MPC
0.44
ClinPred
0.73
D
GERP RS
5.8
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.45
gMVP
0.77

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs976603626; hg19: chr11-6629322; API