10-74013604-C-G

Variant names:

• chr10-74013604-C-G
• rs1403629
• NM_014000.3:c.168+15229C>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_014000.3(VCL):​c.168+15229C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.631 in 151,540 control chromosomes in the GnomAD database, including 31,082 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.63 (31082 hom., cov: 29)
• Consequence: VCL NM_014000.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.110
• Publications: 4 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

ENSG00000225761 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.697 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.168+15229C>G		intron	N/A	NP_054706.1	P18206-1
	VCL	NM_003373.4		c.168+15229C>G		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.168+15229C>G		intron	N/A	ENSP00000211998.5	P18206-1
	VCL	ENST00000372755.7	TSL:1	c.168+15229C>G		intron	N/A	ENSP00000361841.3	P18206-2
	VCL	ENST00000623461.3	TSL:1	n.80-3228C>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.631 AC: 95605 AN: 151424 Hom.: 31075 Cov.: 29

Gnomad AFR AF: 0.552

Gnomad AMI AF: 0.568

Gnomad AMR AF: 0.700

Gnomad ASJ AF: 0.739

Gnomad EAS AF: 0.251

Gnomad SAS AF: 0.439

Gnomad FIN AF: 0.617

Gnomad MID AF: 0.756

Gnomad NFE AF: 0.702

Gnomad OTH AF: 0.676

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.631 AC: 95657 AN: 151540 Hom.: 31082 Cov.: 29 AF XY: 0.625 AC XY: 46249 AN XY: 74038

African (AFR) AF: 0.552 AC: 22787 AN: 41266

American (AMR) AF: 0.699 AC: 10624 AN: 15200

Ashkenazi Jewish (ASJ) AF: 0.739 AC: 2563 AN: 3468

East Asian (EAS) AF: 0.251 AC: 1292 AN: 5144

South Asian (SAS) AF: 0.440 AC: 2108 AN: 4796

European-Finnish (FIN) AF: 0.617 AC: 6457 AN: 10470

Middle Eastern (MID) AF: 0.741 AC: 218 AN: 294

European-Non Finnish (NFE) AF: 0.702 AC: 47679 AN: 67894

Other (OTH) AF: 0.673 AC: 1412 AN: 2098

Alfa AF: 0.562 Hom.: 1617

Bravo AF: 0.631

Asia WGS AF: 0.365 AC: 1271 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	8.6
DANN	Benign	0.65
PhyloP100		0.11
Mutation Taster		=100/0	polymorphism (auto)

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: rs1403629; hg19: chr10-75773362;