rs1908339

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_014000.3(VCL):c.875-24T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.586 in 1,611,454 control chromosomes in the GnomAD database, including 287,558 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). There are indicators that this mutation may affect the branch point..

Frequency

Genomes: 𝑓 0.66 ( 35053 hom., cov: 32)

Exomes 𝑓: 0.58 ( 252505 hom. )

Consequence

VCL
NM_014000.3 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 0.867

Publications

13 publications found

Variant links:

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

VCL links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 3 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.53).

BP6

Variant 10-74083342-T-A is Benign according to our data. Variant chr10-74083342-T-A is described in ClinVar as Benign. ClinVar VariationId is 498457.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.96 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.875-24T>A		intron	N/A	NP_054706.1	P18206-1
	VCL	NM_003373.4		c.875-24T>A		intron	N/A	NP_003364.1	P18206-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
VCL	ENST00000211998.10	TSL:1 MANE Select	c.875-24T>A	intron	N/A	ENSP00000211998.5	P18206-1
VCL	ENST00000372755.7	TSL:1	c.875-24T>A	intron	N/A	ENSP00000361841.3	P18206-2
VCL	ENST00000623461.3	TSL:1	n.3678-24T>A	intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.660

AC:

100388

AN:

152048

Hom.:

34997

Cov.:

show subpopulations

Gnomad AFR

AF:

0.863

Gnomad AMI

AF:

0.543

Gnomad AMR

AF:

0.589

Gnomad ASJ

AF:

0.512

Gnomad EAS

AF:

0.982

Gnomad SAS

AF:

0.778

Gnomad FIN

AF:

0.653

Gnomad MID

AF:

0.570

Gnomad NFE

AF:

0.532

Gnomad OTH

AF:

0.608

GnomAD2 exomes

AF:

0.640

AC:

160777

AN:

251162

AF XY:

0.636

show subpopulations

Gnomad AFR exome

AF:

0.872

Gnomad AMR exome

AF:

0.636

Gnomad ASJ exome

AF:

0.510

Gnomad EAS exome

AF:

0.984

Gnomad FIN exome

AF:

0.644

Gnomad NFE exome

AF:

0.532

Gnomad OTH exome

AF:

0.594

GnomAD4 exome

AF:

0.578

AC:

844096

AN:

1459288

Hom.:

252505

Cov.:

AF XY:

0.582

AC XY:

422335

AN XY:

726082

show subpopulations

African (AFR)

AF:

0.876

AC:

29276

AN:

33430

American (AMR)

AF:

0.633

AC:

28267

AN:

44684

Ashkenazi Jewish (ASJ)

AF:

0.508

AC:

13249

AN:

26088

East Asian (EAS)

AF:

0.989

AC:

39241

AN:

39666

South Asian (SAS)

AF:

0.757

AC:

65230

AN:

86118

European-Finnish (FIN)

AF:

0.646

AC:

34381

AN:

53232

Middle Eastern (MID)

AF:

0.527

AC:

3035

AN:

5760

European-Non Finnish (NFE)

AF:

0.536

AC:

595214

AN:

1110062

Other (OTH)

AF:

0.601

AC:

36203

AN:

60248

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

16068

32136

48205

64273

80341

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

17258

34516

51774

69032

86290

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.660

AC:

100504

AN:

152166

Hom.:

35053

Cov.:

AF XY:

0.668

AC XY:

49680

AN XY:

74398

show subpopulations

African (AFR)

AF:

0.863

AC:

35849

AN:

41544

American (AMR)

AF:

0.590

AC:

9018

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.512

AC:

1774

AN:

3464

East Asian (EAS)

AF:

0.982

AC:

5093

AN:

5184

South Asian (SAS)

AF:

0.776

AC:

3745

AN:

4824

European-Finnish (FIN)

AF:

0.653

AC:

6910

AN:

10580

Middle Eastern (MID)

AF:

0.578

AC:

170

AN:

294

European-Non Finnish (NFE)

AF:

0.532

AC:

36160

AN:

67966

Other (OTH)

AF:

0.611

AC:

1290

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1614

3228

4843

6457

8071

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

798

1596

2394

3192

3990

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.585

Hom.:

5007

Bravo

AF:

0.664

Asia WGS

AF:

0.867

AC:

3013

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (4)

not provided (3)

Dilated cardiomyopathy 1W (1)

Hypertrophic cardiomyopathy 15 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.53

CADD

Benign

(source)

DANN

Benign

0.77

PhyloP100

0.87

BranchPoint Hunter

3.0

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over