rs1555112641

Positions:

• chr10-73998373-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PP2 PP3 BS2

The NM_014000.3(VCL):​c.166C>T​(p.Arg56Trp) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000508 in 1,377,626 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R56Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000051 (0 hom.)
• Consequence: VCL NM_014000.3 missense, splice_region
• Scores: Splicing: ADA: 0.9973
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.95

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 Likely_benign. Variant got -2 ACMG points.

• PP2: Missense variant where missense usually causes diseases, VCL
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• BS2: High AC in GnomAdExome4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VCL	NM_014000.3	c.166C>T	p.Arg56Trp	missense_variant, splice_region_variant	1/22	ENST00000211998.10
VCL	NM_003373.4	c.166C>T	p.Arg56Trp	missense_variant, splice_region_variant	1/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VCL	ENST00000211998.10	c.166C>T	p.Arg56Trp	missense_variant, splice_region_variant	1/22	1	NM_014000.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000508 AC: 7 AN: 1377626 Hom.: 0 Cov.: 31 AF XY: 0.00000295 AC XY: 2 AN XY: 678336

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: 0.00000655

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Dilated cardiomyopathy 1W Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Mar 08, 2017

This sequence change replaces arginine with tryptophan at codon 56 of the VCL protein (p.Arg56Trp). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and tryptophan. While this variant is not present in population databases (no rsID), the frequency information is unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has not been reported in the literature in individuals with a VCL-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.74
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Pathogenic	35
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.46	T;.
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Benign	0.48	N
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Pathogenic	0.41	D
MetaRNN	Pathogenic	0.82	D;D
MetaSVM	Benign	-0.64	T
MutationAssessor	Benign	1.9	L;L
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-4.1	D;D
REVEL	Uncertain	0.33
Sift	Uncertain	0.0010	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	D;D
Vest4		0.77
MutPred		0.50		Gain of catalytic residue at L54 (P = 0.0028);Gain of catalytic residue at L54 (P = 0.0028);
MVP		0.59
MPC		2.4
ClinPred		1.0	D
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.77
gMVP		0.61

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.73
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: rs1555112641; hg19: chr10-75758131;