rs2131956

Variant names:

• chr10-74111977-C-G
• rs2131956
• NM_014000.3:c.2814C>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_014000.3(VCL):​c.2814C>G​(p.Gly938Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.711 in 1,613,952 control chromosomes in the GnomAD database, including 414,207 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.73 (41249 hom., cov: 32)
  • Exomes 𝑓: 0.71 (372958 hom.)
• Consequence: VCL NM_014000.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: 2.39
• Publications: 27 publications found

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 Gene-Disease associations (from GenCC):

• dilated cardiomyopathy

  Inheritance: AD Classification: STRONG Submitted by: ClinGen
• dilated cardiomyopathy 1W

  Inheritance: AD Classification: STRONG, MODERATE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hypertrophic cardiomyopathy 15

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• hypertrophic cardiomyopathy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant 10-74111977-C-G is Benign according to our data. Variant chr10-74111977-C-G is described in ClinVar as Benign. ClinVar VariationId is 45600.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.39 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.778 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014000.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VCL	NM_014000.3	MANE Select	c.2814C>G	p.Gly938Gly	synonymous	Exon 19 of 22	NP_054706.1	P18206-1
	VCL	NM_003373.4		c.2746-2207C>G		intron	N/A	NP_003364.1	P18206-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VCL	ENST00000211998.10	TSL:1 MANE Select	c.2814C>G	p.Gly938Gly	synonymous	Exon 19 of 22	ENSP00000211998.5	P18206-1
	VCL	ENST00000372755.7	TSL:1	c.2746-2207C>G		intron	N/A	ENSP00000361841.3	P18206-2
	VCL	ENST00000623461.3	TSL:1	n.5549-2207C>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.730 AC: 110917 AN: 151978 Hom.: 41216 Cov.: 32

Gnomad AFR AF: 0.785

Gnomad AMI AF: 0.613

Gnomad AMR AF: 0.704

Gnomad ASJ AF: 0.857

Gnomad EAS AF: 0.394

Gnomad SAS AF: 0.533

Gnomad FIN AF: 0.661

Gnomad MID AF: 0.867

Gnomad NFE AF: 0.745

Gnomad OTH AF: 0.774

GnomAD2 exomes AF: 0.669 AC: 168222 AN: 251342 AF XY: 0.670

Gnomad AFR exome AF: 0.780

Gnomad AMR exome AF: 0.582

Gnomad ASJ exome AF: 0.857

Gnomad EAS exome AF: 0.368

Gnomad FIN exome AF: 0.672

Gnomad NFE exome AF: 0.741

Gnomad OTH exome AF: 0.714

GnomAD4 exome AF: 0.709 AC: 1037157 AN: 1461856 Hom.: 372958 Cov.: 85 AF XY: 0.707 AC XY: 513853 AN XY: 727226

African (AFR) AF: 0.784 AC: 26252 AN: 33480

American (AMR) AF: 0.596 AC: 26634 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.857 AC: 22386 AN: 26136

East Asian (EAS) AF: 0.392 AC: 15556 AN: 39698

South Asian (SAS) AF: 0.554 AC: 47785 AN: 86256

European-Finnish (FIN) AF: 0.671 AC: 35835 AN: 53408

Middle Eastern (MID) AF: 0.833 AC: 4807 AN: 5768

European-Non Finnish (NFE) AF: 0.732 AC: 814524 AN: 1112000

Other (OTH) AF: 0.718 AC: 43378 AN: 60396

GnomAD4 genome AF: 0.730 AC: 111003 AN: 152096 Hom.: 41249 Cov.: 32 AF XY: 0.722 AC XY: 53632 AN XY: 74332

African (AFR) AF: 0.786 AC: 32590 AN: 41486

American (AMR) AF: 0.703 AC: 10748 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.857 AC: 2974 AN: 3470

East Asian (EAS) AF: 0.394 AC: 2033 AN: 5154

South Asian (SAS) AF: 0.535 AC: 2573 AN: 4812

European-Finnish (FIN) AF: 0.661 AC: 6988 AN: 10568

Middle Eastern (MID) AF: 0.850 AC: 250 AN: 294

European-Non Finnish (NFE) AF: 0.745 AC: 50669 AN: 68004

Other (OTH) AF: 0.768 AC: 1620 AN: 2110

Alfa AF: 0.755 Hom.: 14131

Bravo AF: 0.731

Asia WGS AF: 0.481 AC: 1676 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (8)
-	-	3	Dilated cardiomyopathy 1W (3)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Hypertrophic cardiomyopathy 15 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	9.1
DANN	Benign	0.67
PhyloP100		2.4
Mutation Taster		=100/0	polymorphism (auto)

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: rs2131956; hg19: chr10-75871735; COSMIC: COSV53009612; COSMIC: COSV53009612;