rs71579355

Positions:

• chr10-74090163-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Moderate BP6 BP7 BS1 BS2

The NM_014000.3(VCL):​c.1317T>C​(p.Ser439Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00536 in 1,614,224 control chromosomes in the GnomAD database, including 31 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0043 (6 hom., cov: 32)
  • Exomes 𝑓: 0.0055 (25 hom.)
• Consequence: VCL NM_014000.3 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:13
• Conservation: PhyloP100: 0.526

Genes affected

VCL (HGNC:12665): (vinculin) Vinculin is a cytoskeletal protein associated with cell-cell and cell-matrix junctions, where it is thought to function as one of several interacting proteins involved in anchoring F-actin to the membrane. Defects in VCL are the cause of cardiomyopathy dilated type 1W. Dilated cardiomyopathy is a disorder characterized by ventricular dilation and impaired systolic function, resulting in congestive heart failure and arrhythmia. Multiple alternatively spliced transcript variants have been found for this gene, but the biological validity of some variants has not been determined. [provided by RefSeq, Jul 2008]

VCL (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 10-74090163-T-C is Benign according to our data. Variant chr10-74090163-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 45577.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1, Benign=7}. Variant chr10-74090163-T-C is described in Lovd as [Benign]. Variant chr10-74090163-T-C is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.526 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0043 (655/152348) while in subpopulation AMR AF= 0.00797 (122/15306). AF 95% confidence interval is 0.00682. There are 6 homozygotes in gnomad4. There are 297 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 655 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VCL	NM_014000.3	c.1317T>C	p.Ser439Ser	synonymous_variant	10/22	ENST00000211998.10	NP_054706.1
VCL	NM_003373.4	c.1317T>C	p.Ser439Ser	synonymous_variant	10/21		NP_003364.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VCL	ENST00000211998.10	c.1317T>C	p.Ser439Ser	synonymous_variant	10/22	1	NM_014000.3	ENSP00000211998.5

Frequencies

GnomAD3 genomes AF: 0.00430 AC: 655 AN: 152230 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.00140

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.00798

Gnomad ASJ AF: 0.00461

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.000376

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00620

Gnomad OTH AF: 0.00907

GnomAD3 exomes AF: 0.00429 AC: 1080 AN: 251482 Hom.: 5 AF XY: 0.00436 AC XY: 592 AN XY: 135918

Gnomad AFR exome AF: 0.000738

Gnomad AMR exome AF: 0.00515

Gnomad ASJ exome AF: 0.00546

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00203

Gnomad FIN exome AF: 0.000647

Gnomad NFE exome AF: 0.00644

Gnomad OTH exome AF: 0.00424

GnomAD4 exome AF: 0.00547 AC: 7998 AN: 1461876 Hom.: 25 Cov.: 31 AF XY: 0.00552 AC XY: 4013 AN XY: 727234

Gnomad4 AFR exome AF: 0.000896

Gnomad4 AMR exome AF: 0.00557

Gnomad4 ASJ exome AF: 0.00486

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00211

Gnomad4 FIN exome AF: 0.000618

Gnomad4 NFE exome AF: 0.00635

Gnomad4 OTH exome AF: 0.00452

GnomAD4 genome AF: 0.00430 AC: 655 AN: 152348 Hom.: 6 Cov.: 32 AF XY: 0.00399 AC XY: 297 AN XY: 74500

Gnomad4 AFR AF: 0.00139

Gnomad4 AMR AF: 0.00797

Gnomad4 ASJ AF: 0.00461

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00207

Gnomad4 FIN AF: 0.000376

Gnomad4 NFE AF: 0.00620

Gnomad4 OTH AF: 0.00898

Alfa AF: 0.00523 Hom.: 1

Bravo AF: 0.00462

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00682

EpiControl AF: 0.00788

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:13

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 30, 2014	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 16, 2012	Ser439Ser in exon 10 of VCL: This variant is not expected to have clinical sign ificance because it does not alter an amino acid residue and has been identified in 0.5% (37/7020) of European American chromosomes from a broad population by t he NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS; dbSNP rs715 79355). -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 12, 2015	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided Benign:5

Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 28, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2024	VCL: BP4, BS2 -

Dilated cardiomyopathy 1W Uncertain:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Cardiomyopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Feb 28, 2017

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 01, 2016

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Benign	8.4
DANN	Benign	0.75
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

Publications

LitVar

Other links and lift over

dbSNP: rs71579355; hg19: chr10-75849921;