rs4746172

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr10-74096084-C-T
• chr10-74096084-C-G

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 19 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

  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

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

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.1743+229C>T		intron	N/A	NP_054706.1	P18206-1
	VCL	NM_003373.4		c.1743+229C>T		intron	N/A	NP_003364.1	P18206-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VCL	ENST00000211998.10	TSL:1 MANE Select	c.1743+229C>T		intron	N/A	ENSP00000211998.5	P18206-1
	VCL	ENST00000372755.7	TSL:1	c.1743+229C>T		intron	N/A	ENSP00000361841.3	P18206-2
	VCL	ENST00000623461.3	TSL:1	n.4546+229C>T		intron	N/A

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

African (AFR) AF: 0.741 AC: 30619 AN: 41330

American (AMR) AF: 0.708 AC: 10801 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.861 AC: 2987 AN: 3470

East Asian (EAS) AF: 0.381 AC: 1958 AN: 5142

South Asian (SAS) AF: 0.541 AC: 2596 AN: 4800

European-Finnish (FIN) AF: 0.665 AC: 6907 AN: 10388

Middle Eastern (MID) AF: 0.846 AC: 247 AN: 292

European-Non Finnish (NFE) AF: 0.752 AC: 51069 AN: 67900

Other (OTH) AF: 0.768 AC: 1613 AN: 2100

Alfa AF: 0.742 Hom.: 6993

Bravo AF: 0.721

Asia WGS AF: 0.477 AC: 1663 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.21
DANN	Benign	0.44
PhyloP100		-2.3
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: rs4746172; hg19: chr10-75855842;