10-73998025-C-T

Variant names:

• chr10-73998025-C-T
• rs546209689
• ENST00000623461.3:n.79+804C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Moderate BP6_Very_Strong BS2

The ENST00000623461.3(VCL):​n.79+804C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000637 in 923,736 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0026 (4 hom., cov: 33)
  • Exomes 𝑓: 0.00025 (0 hom.)
• Consequence: VCL ENST00000623461.3 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.78
• 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

  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=-0.46).
• BP6: Variant 10-73998025-C-T is Benign according to our data. Variant chr10-73998025-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1205590.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 398 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000623461.3. 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.-183C>T		upstream_gene	N/A	NP_054706.1	P18206-1
	VCL	NM_003373.4		c.-183C>T		upstream_gene	N/A	NP_003364.1	P18206-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VCL	ENST00000623461.3	TSL:1	n.79+804C>T		intron	N/A
	VCL	ENST00000211998.10	TSL:1 MANE Select	c.-183C>T		upstream_gene	N/A	ENSP00000211998.5	P18206-1
	VCL	ENST00000372755.7	TSL:1	c.-183C>T		upstream_gene	N/A	ENSP00000361841.3	P18206-2

Frequencies

GnomAD3 genomes AF: 0.00262 AC: 398 AN: 152136 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.00924

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000523

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00143

GnomAD4 exome AF: 0.000246 AC: 190 AN: 771484 Hom.: 0 AF XY: 0.000156 AC XY: 61 AN XY: 392014

African (AFR) AF: 0.00724 AC: 140 AN: 19344

American (AMR) AF: 0.000581 AC: 16 AN: 27522

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17380

East Asian (EAS) AF: 0.00 AC: 0 AN: 31744

South Asian (SAS) AF: 0.0000348 AC: 2 AN: 57418

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 30514

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2740

European-Non Finnish (NFE) AF: 0.00000730 AC: 4 AN: 548074

Other (OTH) AF: 0.000762 AC: 28 AN: 36748

GnomAD4 genome AF: 0.00261 AC: 398 AN: 152252 Hom.: 4 Cov.: 33 AF XY: 0.00257 AC XY: 191 AN XY: 74442

African (AFR) AF: 0.00922 AC: 383 AN: 41554

American (AMR) AF: 0.000523 AC: 8 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5162

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 67996

Other (OTH) AF: 0.00142 AC: 3 AN: 2116

Alfa AF: 0.00235 Hom.: 0

Bravo AF: 0.00321

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	1.3
DANN	Benign	0.89
PhyloP100		-1.8
PromoterAI		0.17	Neutral

Splicing

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

Other links and lift over

dbSNP: rs546209689; hg19: chr10-75757783;