10-74107875-T-C

Variant names:

• chr10-74107875-T-C
• rs1874150
• NM_014000.3:c.2559+521T>C

Variant summary

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

The NM_014000.3(VCL):​c.2559+521T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.677 in 151,976 control chromosomes in the GnomAD database, including 35,612 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 0.68 (35612 hom., cov: 31)
• Consequence: VCL NM_014000.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.09
• Publications: 5 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.739 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VCL	NM_014000.3	MANE Select	c.2559+521T>C		intron	N/A	NP_054706.1
	VCL	NM_003373.4		c.2559+521T>C		intron	N/A	NP_003364.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VCL	ENST00000211998.10	TSL:1 MANE Select	c.2559+521T>C		intron	N/A	ENSP00000211998.5
	VCL	ENST00000372755.7	TSL:1	c.2559+521T>C		intron	N/A	ENSP00000361841.3
	VCL	ENST00000623461.3	TSL:1	n.5362+521T>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.677 AC: 102834 AN: 151858 Hom.: 35600 Cov.: 31

Gnomad AFR AF: 0.603

Gnomad AMI AF: 0.612

Gnomad AMR AF: 0.681

Gnomad ASJ AF: 0.853

Gnomad EAS AF: 0.394

Gnomad SAS AF: 0.533

Gnomad FIN AF: 0.660

Gnomad MID AF: 0.845

Gnomad NFE AF: 0.745

Gnomad OTH AF: 0.742

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

GnomAD4 genome AF: 0.677 AC: 102886 AN: 151976 Hom.: 35612 Cov.: 31 AF XY: 0.671 AC XY: 49846 AN XY: 74274

African (AFR) AF: 0.603 AC: 24997 AN: 41434

American (AMR) AF: 0.680 AC: 10386 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.853 AC: 2958 AN: 3468

East Asian (EAS) AF: 0.395 AC: 2041 AN: 5172

South Asian (SAS) AF: 0.534 AC: 2560 AN: 4794

European-Finnish (FIN) AF: 0.660 AC: 6956 AN: 10532

Middle Eastern (MID) AF: 0.830 AC: 244 AN: 294

European-Non Finnish (NFE) AF: 0.745 AC: 50633 AN: 67984

Other (OTH) AF: 0.736 AC: 1553 AN: 2110

Alfa AF: 0.708 Hom.: 4957

Bravo AF: 0.670

Asia WGS AF: 0.474 AC: 1652 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	2.3
DANN	Benign	0.51
PhyloP100		-1.1
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: rs1874150; hg19: chr10-75867633;