rs703258

Variant names:

• chr10-74119753-T-A
• rs703258
• ENST00000623461.3:n.7588T>A

Your query was ambiguous. Multiple possible variants found:

• chr10-74119753-T-A
• chr10-74119753-T-G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000623461.3(VCL):​n.7588T>A variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.733 in 152,428 control chromosomes in the GnomAD database, including 41,710 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.73 (41618 hom., cov: 31)
  • Exomes 𝑓: 0.66 (92 hom.)
• Consequence: VCL ENST00000623461.3 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.26
• Publications: 14 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 10-74119753-T-A is Benign according to our data. Variant chr10-74119753-T-A is described in ClinVar as Benign. ClinVar VariationId is 300815.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.78 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VCL	NM_014000.3	c.*1584T>A		3_prime_UTR_variant	Exon 22 of 22	ENST00000211998.10	NP_054706.1
VCL	NM_003373.4	c.*1584T>A		3_prime_UTR_variant	Exon 21 of 21		NP_003364.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VCL	ENST00000623461.3	n.7588T>A		non_coding_transcript_exon_variant	Exon 23 of 23	1
VCL	ENST00000211998.10	c.*1584T>A		3_prime_UTR_variant	Exon 22 of 22	1	NM_014000.3	ENSP00000211998.5
VCL	ENST00000372755.7	c.*1584T>A		3_prime_UTR_variant	Exon 21 of 21	1		ENSP00000361841.3

Frequencies

GnomAD3 genomes AF: 0.733 AC: 111398 AN: 151890 Hom.: 41585 Cov.: 31

Gnomad AFR AF: 0.787

Gnomad AMI AF: 0.694

Gnomad AMR AF: 0.706

Gnomad ASJ AF: 0.857

Gnomad EAS AF: 0.394

Gnomad SAS AF: 0.536

Gnomad FIN AF: 0.664

Gnomad MID AF: 0.867

Gnomad NFE AF: 0.750

Gnomad OTH AF: 0.778

GnomAD4 exome AF: 0.662 AC: 278 AN: 420 Hom.: 92 Cov.: 0 AF XY: 0.684 AC XY: 171 AN XY: 250

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.658 AC: 271 AN: 412

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 1.00 AC: 2 AN: 2

Other (OTH) AF: 0.833 AC: 5 AN: 6

GnomAD4 genome AF: 0.733 AC: 111483 AN: 152008 Hom.: 41618 Cov.: 31 AF XY: 0.725 AC XY: 53820 AN XY: 74270

African (AFR) AF: 0.787 AC: 32624 AN: 41444

American (AMR) AF: 0.705 AC: 10765 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.857 AC: 2976 AN: 3472

East Asian (EAS) AF: 0.394 AC: 2036 AN: 5164

South Asian (SAS) AF: 0.537 AC: 2590 AN: 4824

European-Finnish (FIN) AF: 0.664 AC: 6993 AN: 10538

Middle Eastern (MID) AF: 0.850 AC: 250 AN: 294

European-Non Finnish (NFE) AF: 0.750 AC: 50992 AN: 67980

Other (OTH) AF: 0.771 AC: 1624 AN: 2106

Alfa AF: 0.745 Hom.: 5267

Bravo AF: 0.735

Asia WGS AF: 0.488 AC: 1701 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Dilated cardiomyopathy 1W Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	7.4
DANN	Benign	0.44
PhyloP100		1.3
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: rs703258; hg19: chr10-75879511; COSMIC: COSV53011652; COSMIC: COSV53011652;