15-42410952-G-A
Variant summary
Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2
The NM_000070.3(CAPN3):c.2332G>A(p.Asp778Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00158 in 1,614,140 control chromosomes in the GnomAD database, including 37 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Consequence
NM_000070.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -20 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
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CAPN3 | ENST00000397163.8 | c.2332G>A | p.Asp778Asn | missense_variant | Exon 22 of 24 | 1 | NM_000070.3 | ENSP00000380349.3 | ||
CAPN3 | ENST00000673886.1 | c.337G>A | p.Asp113Asn | missense_variant | Exon 9 of 11 | ENSP00000501155.1 | ||||
CAPN3 | ENST00000673928.1 | c.337G>A | p.Asp113Asn | missense_variant | Exon 9 of 11 | ENSP00000501099.1 | ||||
CAPN3 | ENST00000674146.1 | c.337G>A | p.Asp113Asn | missense_variant | Exon 10 of 12 | ENSP00000501175.1 | ||||
CAPN3 | ENST00000674149.1 | c.337G>A | p.Asp113Asn | missense_variant | Exon 9 of 11 | ENSP00000501112.1 | ||||
CAPN3 | ENST00000673743.1 | c.235G>A | p.Asp79Asn | missense_variant | Exon 9 of 11 | ENSP00000500989.1 | ||||
ENSG00000258461 | ENST00000495723.1 | n.*2768G>A | non_coding_transcript_exon_variant | Exon 24 of 26 | 2 | ENSP00000492063.1 | ||||
ENSG00000258461 | ENST00000495723.1 | n.*2768G>A | 3_prime_UTR_variant | Exon 24 of 26 | 2 | ENSP00000492063.1 |
Frequencies
GnomAD3 genomes AF: 0.00822 AC: 1251AN: 152178Hom.: 26 Cov.: 31
GnomAD3 exomes AF: 0.00222 AC: 557AN: 251396Hom.: 8 AF XY: 0.00154 AC XY: 209AN XY: 135856
GnomAD4 exome AF: 0.000889 AC: 1299AN: 1461844Hom.: 11 Cov.: 32 AF XY: 0.000759 AC XY: 552AN XY: 727232
GnomAD4 genome AF: 0.00822 AC: 1252AN: 152296Hom.: 26 Cov.: 31 AF XY: 0.00779 AC XY: 580AN XY: 74474
ClinVar
Submissions by phenotype
Autosomal recessive limb-girdle muscular dystrophy type 2A Pathogenic:1Benign:4
This mutation has been reported in 1000 genomes and ExAC databases with minor allele frequency of 0.9% and 0.28%. The in silico prediction of this variant is damaging by Mutation Taster2. -
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This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
not specified Benign:5
Variant summary: CAPN3 c.2332G>A (p.Asp778Asn) results in a conservative amino acid change located in the penta-EF-hand domain (IPR029531) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0022 in 251396 control chromosomes, predominantly at a frequency of 0.031 within the African or African-American subpopulation in the gnomAD database, including 7 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 10-fold of the estimated maximal expected allele frequency for a pathogenic variant in CAPN3 causing an autosomal recessive Limb-Girdle Muscular Dystrophy phenotype (0.0032), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.2332G>A has been reported in the literature in the compound heterozygous state in one individual affected with Limb-Girdle Muscular Dystrophy (Pathak_2021). This report does not provide unequivocal conclusions about association of the variant with Limb-Girdle Muscular Dystrophy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven submitters have provided clinical-significance assessments for this variant to ClinVar after 2014. The majority classified the variant as benign (n=3)/likely benign (n=3) and one classified it as pathogenic. Based on the evidence outlined above, the variant was classified as benign. -
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Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
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. -
not provided Benign:2
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at