10-74111990-C-G
Variant summary
Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2
The NM_014000.3(VCL):c.2827C>G(p.Pro943Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000181 in 1,614,076 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P943T) has been classified as Uncertain significance.
Frequency
Consequence
NM_014000.3 missense
Scores
Clinical Significance
Conservation
Publications
- dilated cardiomyopathy 1WInheritance: AD Classification: STRONG, MODERATE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
- dilated cardiomyopathyInheritance: AD Classification: MODERATE Submitted by: ClinGen
- familial isolated dilated cardiomyopathyInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- hypertrophic cardiomyopathy 15Inheritance: AD Classification: LIMITED Submitted by: PanelApp Australia, Ambry Genetics, Labcorp Genetics (formerly Invitae)
- hypertrophic cardiomyopathyInheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
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ACMG classification
Our verdict: Benign. The variant received -16 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000112 AC: 17AN: 152184Hom.: 0 Cov.: 32 show subpopulations
GnomAD2 exomes AF: 0.000191 AC: 48AN: 251460 AF XY: 0.000206 show subpopulations
GnomAD4 exome AF: 0.000188 AC: 275AN: 1461892Hom.: 1 Cov.: 35 AF XY: 0.000199 AC XY: 145AN XY: 727246 show subpopulations
GnomAD4 genome AF: 0.000112 AC: 17AN: 152184Hom.: 0 Cov.: 32 AF XY: 0.000121 AC XY: 9AN XY: 74340 show subpopulations
ClinVar
Submissions by phenotype
not provided Benign:3
In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Reported in ClinVar but additional evidence is not available (ClinVar Variant ID# 192181; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 23861362, 15769782, 25351510, 16236538) -
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not specified Benign:1
BS1, BS4_supp, BP4, BP6 -
Cardiomyopathy Benign:1
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Dilated cardiomyopathy 1W Benign:1
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Cardiovascular phenotype Benign:1
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at