NM_014000.3:c.2841C>A

Variant names:

• chr10-74112004-C-A
• NM_014000.3:c.2841C>A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_014000.3(VCL):​c.2841C>A​(p.Asp947Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,894 control chromosomes in the GnomAD database, with no homozygous occurrence. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: VCL NM_014000.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.92

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VCL	NM_014000.3	c.2841C>A	p.Asp947Glu	missense_variant	Exon 19 of 22	ENST00000211998.10	NP_054706.1
VCL	NM_003373.4	c.2746-2180C>A		intron_variant	Intron 18 of 20		NP_003364.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VCL	ENST00000211998.10	c.2841C>A	p.Asp947Glu	missense_variant	Exon 19 of 22	1	NM_014000.3	ENSP00000211998.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461894 Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0 AN XY: 727248

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.055	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.085	T
Eigen	Benign	0.12
Eigen_PC	Benign	0.17
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.018	T
MetaRNN	Uncertain	0.47	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.55	N
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-0.010	N
REVEL	Benign	0.20
Sift	Uncertain	0.024	D
Sift4G	Benign	0.53	T
Polyphen		0.93	P
Vest4		0.61
MutPred		0.38		Gain of loop (P = 0.0079);
MVP		0.36
MPC		0.047
ClinPred		0.57	D
GERP RS		3.3
Varity_R		0.087
gMVP		0.26

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr10-75871762;