rs16931179

Variant names:

• chr10-74111964-C-T
• rs16931179
• NM_014000.3:c.2801C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_014000.3(VCL):​c.2801C>T​(p.Ala934Val) variant causes a missense change. The variant allele was found at a frequency of 0.00492 in 1,614,188 control chromosomes in the GnomAD database, including 209 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A934A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0076 (34 hom., cov: 32)
  • Exomes 𝑓: 0.0046 (175 hom.)
• Consequence: VCL NM_014000.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:17 O:1
• Conservation: PhyloP100: 4.38
• Publications: 23 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0017710626).
• BP6: Variant 10-74111964-C-T is Benign according to our data. Variant chr10-74111964-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 45599.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0709 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.2801C>T	p.Ala934Val	missense	Exon 19 of 22	NP_054706.1	P18206-1
	VCL	NM_003373.4		c.2746-2220C>T		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.2801C>T	p.Ala934Val	missense	Exon 19 of 22	ENSP00000211998.5	P18206-1
	VCL	ENST00000372755.7	TSL:1	c.2746-2220C>T		intron	N/A	ENSP00000361841.3	P18206-2
	VCL	ENST00000623461.3	TSL:1	n.5549-2220C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00751 AC: 1143 AN: 152182 Hom.: 32 Cov.: 32

Gnomad AFR AF: 0.000844

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0162

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0773

Gnomad SAS AF: 0.00496

Gnomad FIN AF: 0.0337

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00101

Gnomad OTH AF: 0.00334

GnomAD2 exomes AF: 0.0141 AC: 3546 AN: 251458 AF XY: 0.0122

Gnomad AFR exome AF: 0.000738

Gnomad AMR exome AF: 0.0329

Gnomad ASJ exome AF: 0.000992

Gnomad EAS exome AF: 0.0796

Gnomad FIN exome AF: 0.0321

Gnomad NFE exome AF: 0.000888

Gnomad OTH exome AF: 0.0121

GnomAD4 exome AF: 0.00465 AC: 6795 AN: 1461888 Hom.: 175 Cov.: 30 AF XY: 0.00439 AC XY: 3194 AN XY: 727246

African (AFR) AF: 0.000209 AC: 7 AN: 33480

American (AMR) AF: 0.0313 AC: 1400 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000995 AC: 26 AN: 26136

East Asian (EAS) AF: 0.0728 AC: 2891 AN: 39700

South Asian (SAS) AF: 0.00225 AC: 194 AN: 86258

European-Finnish (FIN) AF: 0.0302 AC: 1612 AN: 53418

Middle Eastern (MID) AF: 0.000867 AC: 5 AN: 5768

European-Non Finnish (NFE) AF: 0.000263 AC: 292 AN: 1112008

Other (OTH) AF: 0.00609 AC: 368 AN: 60396

GnomAD4 genome AF: 0.00756 AC: 1151 AN: 152300 Hom.: 34 Cov.: 32 AF XY: 0.00975 AC XY: 726 AN XY: 74484

African (AFR) AF: 0.000842 AC: 35 AN: 41570

American (AMR) AF: 0.0165 AC: 253 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.0771 AC: 400 AN: 5186

South Asian (SAS) AF: 0.00497 AC: 24 AN: 4830

European-Finnish (FIN) AF: 0.0337 AC: 358 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00101 AC: 69 AN: 68010

Other (OTH) AF: 0.00567 AC: 12 AN: 2116

Alfa AF: 0.00410 Hom.: 39

Bravo AF: 0.00780

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.0121 AC: 1472

EpiCase AF: 0.000491

EpiControl AF: 0.000296

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	9	not specified (9)
-	-	4	not provided (4)
-	-	2	Dilated cardiomyopathy 1W (2)
-	-	1	Cardiomyopathy (1)
-	-	1	Cardiovascular phenotype (1)
-	-	-	Dilated cardiomyopathy 1W;C2750459:Hypertrophic cardiomyopathy 15 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	19
DANN	Benign	0.48
DEOGEN2	Benign	0.092	T
Eigen	Benign	-0.18
Eigen_PC	Benign	0.046
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.69	T
MetaRNN	Benign	0.0018	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N
PhyloP100		4.4
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.33	N
REVEL	Benign	0.061
Sift	Benign	0.28	T
Sift4G	Benign	0.30	T
Polyphen		0.0010	B
Vest4		0.085
MPC		0.047
ClinPred		0.0084	T
GERP RS		5.3
Varity_R		0.064
gMVP		0.33
Mutation Taster		=50/50	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: rs16931179; hg19: chr10-75871722; COSMIC: COSV53009600; COSMIC: COSV53009600;