rs143702799

Variant names:

• chr10-74071076-T-G
• rs143702799
• NM_014000.3:c.492T>G

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6 BP7 BS2

The NM_014000.3(VCL):​c.492T>G​(p.Leu164Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000597 in 1,614,050 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00034 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00062 (3 hom.)
• Consequence: VCL NM_014000.3 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:12
• Conservation: PhyloP100: 2.71
• Publications: 3 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: Labcorp Genetics (formerly Invitae), Ambry Genetics
• 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: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BP6: Variant 10-74071076-T-G is Benign according to our data. Variant chr10-74071076-T-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 166536.
• BP7: Synonymous conserved (PhyloP=2.71 with no splicing effect.
• BS2: High AC in GnomAd4 at 52 AD gene.

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.492T>G	p.Leu164Leu	synonymous	Exon 4 of 22	NP_054706.1	P18206-1
	VCL	NM_003373.4		c.492T>G	p.Leu164Leu	synonymous	Exon 4 of 21	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.492T>G	p.Leu164Leu	synonymous	Exon 4 of 22	ENSP00000211998.5	P18206-1
	VCL	ENST00000372755.7	TSL:1	c.492T>G	p.Leu164Leu	synonymous	Exon 4 of 21	ENSP00000361841.3	P18206-2
	VCL	ENST00000623461.3	TSL:1	n.450T>G		non_coding_transcript_exon	Exon 6 of 23

Frequencies

GnomAD3 genomes AF: 0.000342 AC: 52 AN: 152196 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000559

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.000334 AC: 84 AN: 251352 AF XY: 0.000383

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.0000868

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000387

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000623 AC: 911 AN: 1461736 Hom.: 3 Cov.: 32 AF XY: 0.000620 AC XY: 451 AN XY: 727180

African (AFR) AF: 0.0000299 AC: 1 AN: 33476

American (AMR) AF: 0.0000671 AC: 3 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39684

South Asian (SAS) AF: 0.00102 AC: 88 AN: 86256

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53410

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000714 AC: 794 AN: 1111904

Other (OTH) AF: 0.000397 AC: 24 AN: 60384

GnomAD4 genome AF: 0.000341 AC: 52 AN: 152314 Hom.: 0 Cov.: 32 AF XY: 0.000242 AC XY: 18 AN XY: 74484

African (AFR) AF: 0.0000962 AC: 4 AN: 41564

American (AMR) AF: 0.000261 AC: 4 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5190

South Asian (SAS) AF: 0.000829 AC: 4 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

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

European-Non Finnish (NFE) AF: 0.000559 AC: 38 AN: 68026

Other (OTH) AF: 0.000474 AC: 1 AN: 2110

Alfa AF: 0.000542 Hom.: 0

Bravo AF: 0.000246

EpiCase AF: 0.000382

EpiControl AF: 0.000593

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	7	not provided (7)
-	1	1	Dilated cardiomyopathy 1W (2)
-	-	2	not specified (2)
-	-	1	Cardiovascular phenotype (1)
-	-	1	VCL-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	8.1
DANN	Benign	0.81
PhyloP100		2.7
Mutation Taster		=95/5	polymorphism

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

Other links and lift over

dbSNP: rs143702799; hg19: chr10-75830834;