10-74096084-C-T

Variant names:

• chr10-74096084-C-T
• rs4746172
• NM_014000.3:c.1743+229C>T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_014000.3(VCL):​c.1743+229C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.722 in 151,586 control chromosomes in the GnomAD database, including 40,149 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.72 (40149 hom., cov: 30)
• Consequence: VCL NM_014000.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.33

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 10-74096084-C-T is Benign according to our data. Variant chr10-74096084-C-T is described in ClinVar as [Benign]. Clinvar id is 678031.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.747 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VCL	NM_014000.3	c.1743+229C>T		intron_variant	Intron 12 of 21	ENST00000211998.10	NP_054706.1
VCL	NM_003373.4	c.1743+229C>T		intron_variant	Intron 12 of 20		NP_003364.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VCL	ENST00000211998.10	c.1743+229C>T		intron_variant	Intron 12 of 21	1	NM_014000.3	ENSP00000211998.5

Frequencies

GnomAD3 genomes AF: 0.722 AC: 109365 AN: 151478 Hom.: 40130 Cov.: 30

Gnomad AFR AF: 0.741

Gnomad AMI AF: 0.694

Gnomad AMR AF: 0.709

Gnomad ASJ AF: 0.861

Gnomad EAS AF: 0.380

Gnomad SAS AF: 0.540

Gnomad FIN AF: 0.665

Gnomad MID AF: 0.854

Gnomad NFE AF: 0.752

Gnomad OTH AF: 0.774

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

GnomAD4 genome AF: 0.722 AC: 109430 AN: 151586 Hom.: 40149 Cov.: 30 AF XY: 0.714 AC XY: 52886 AN XY: 74030

Gnomad4 AFR AF: 0.741

Gnomad4 AMR AF: 0.708

Gnomad4 ASJ AF: 0.861

Gnomad4 EAS AF: 0.381

Gnomad4 SAS AF: 0.541

Gnomad4 FIN AF: 0.665

Gnomad4 NFE AF: 0.752

Gnomad4 OTH AF: 0.768

Alfa AF: 0.741 Hom.: 6761

Bravo AF: 0.721

Asia WGS AF: 0.477 AC: 1663 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jun 14, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.21
DANN	Benign	0.44

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

Publications

LitVar

Other links and lift over

dbSNP: rs4746172; hg19: chr10-75855842;