10-73998384-G-T

Variant names:

• chr10-73998384-G-T
• rs997516030
• NM_014000.3:c.168+9G>T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 2P and 10B. PM2 BP4_Moderate BP6_Very_Strong

The NM_014000.3(VCL):​c.168+9G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.4e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: VCL NM_014000.3 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.861
• Publications: 0 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 -8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.21).
• BP6: Variant 10-73998384-G-T is Benign according to our data. Variant chr10-73998384-G-T is described in ClinVar as Likely_benign. ClinVar VariationId is 505151.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VCL	NM_014000.3	c.168+9G>T		intron_variant	Intron 1 of 21	ENST00000211998.10	NP_054706.1
VCL	NM_003373.4	c.168+9G>T		intron_variant	Intron 1 of 20		NP_003364.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VCL	ENST00000211998.10	c.168+9G>T		intron_variant	Intron 1 of 21	1	NM_014000.3	ENSP00000211998.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000886 AC: 1 AN: 112880 AF XY: 0.0000160

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 7.39e-7 AC: 1 AN: 1353998 Hom.: 0 Cov.: 31 AF XY: 0.00000150 AC XY: 1 AN XY: 665430

African (AFR) AF: 0.00 AC: 0 AN: 28168

American (AMR) AF: 0.00 AC: 0 AN: 30518

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23730

East Asian (EAS) AF: 0.00 AC: 0 AN: 32046

South Asian (SAS) AF: 0.00 AC: 0 AN: 75782

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46116

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5038

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1056820

Other (OTH) AF: 0.0000179 AC: 1 AN: 55780

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ClinVar

Significance: Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Jun 24, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

c.168+9G>T in intron 1 of VCL: This variant is not expected to have clinical sig nificance because it is not located within the splice consensus sequence.

Dilated cardiomyopathy 1W Benign:1

Oct 15, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:1

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.21
CADD	Benign	14
DANN	Benign	0.93
PhyloP100		0.86
PromoterAI		-0.046	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2

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: rs997516030; hg19: chr10-75758142;