rs551463686

Variant names:

• chr10-74108971-C-A
• rs551463686
• NM_014000.3:c.2560C>A

Your query was ambiguous. Multiple possible variants found:

• chr10-74108971-C-A
• chr10-74108971-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_014000.3(VCL):​c.2560C>A​(p.Leu854Ile) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 17/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. L854L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: VCL NM_014000.3 missense, splice_region
• Scores: Splicing: ADA: 0.0007382
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.08
• Publications: 0 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 1W

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

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen
• familial isolated dilated cardiomyopathy

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

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

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15401298).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VCL	NM_014000.3	c.2560C>A	p.Leu854Ile	missense_variant, splice_region_variant	Exon 18 of 22	ENST00000211998.10	NP_054706.1
VCL	NM_003373.4	c.2560C>A	p.Leu854Ile	missense_variant, splice_region_variant	Exon 18 of 21		NP_003364.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VCL	ENST00000211998.10	c.2560C>A	p.Leu854Ile	missense_variant, splice_region_variant	Exon 18 of 22	1	NM_014000.3	ENSP00000211998.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251460 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	19
DANN	Benign	0.88
DEOGEN2	Benign	0.079	T;.
Eigen	Benign	-0.13
Eigen_PC	Benign	0.067
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.90	D;D
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.15	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.3	L;L
PhyloP100		2.1
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	0.11	N;N
REVEL	Benign	0.031
Sift	Benign	0.42	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.067	B;B
Vest4		0.31
MutPred		0.33		Gain of helix (P = 0.1736);Gain of helix (P = 0.1736);
MVP		0.30
MPC		0.46
ClinPred		0.12	T
GERP RS		4.7
Varity_R		0.14
gMVP		0.14
Mutation Taster		=60/40	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00074
dbscSNV1_RF	Benign	0.020
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

Other links and lift over

dbSNP: rs551463686; hg19: chr10-75868729;