rs62642519

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000070.3(CAPN3):​c.78G>A​(p.Pro26Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00302 in 1,614,128 control chromosomes in the GnomAD database, including 127 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.017 ( 74 hom., cov: 32)
Exomes 𝑓: 0.0016 ( 53 hom. )

Consequence

CAPN3
NM_000070.3 synonymous

Scores

2

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -1.01
Variant links:
Genes affected
CAPN3 (HGNC:1480): (calpain 3) Calpain, a heterodimer consisting of a large and a small subunit, is a major intracellular protease, although its function has not been well established. This gene encodes a muscle-specific member of the calpain large subunit family that specifically binds to titin. Mutations in this gene are associated with limb-girdle muscular dystrophies type 2A. Alternate promoters and alternative splicing result in multiple transcript variants encoding different isoforms and some variants are ubiquitously expressed. [provided by RefSeq, Jul 2008]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.82).
BP6
Variant 15-42359883-G-A is Benign according to our data. Variant chr15-42359883-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 128574.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-42359883-G-A is described in Lovd as [Benign].
BP7
Synonymous conserved (PhyloP=-1.01 with no splicing effect.
BA1
GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0568 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CAPN3NM_000070.3 linkc.78G>A p.Pro26Pro synonymous_variant Exon 1 of 24 ENST00000397163.8 NP_000061.1 P20807-1
CAPN3NM_024344.2 linkc.78G>A p.Pro26Pro synonymous_variant Exon 1 of 23 NP_077320.1 P20807-3
CAPN3NM_173087.2 linkc.78G>A p.Pro26Pro synonymous_variant Exon 1 of 21 NP_775110.1 P20807-2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CAPN3ENST00000397163.8 linkc.78G>A p.Pro26Pro synonymous_variant Exon 1 of 24 1 NM_000070.3 ENSP00000380349.3 P20807-1
ENSG00000258461ENST00000495723.1 linkn.*105+5430G>A intron_variant Intron 5 of 25 2 ENSP00000492063.1 A0A1W2PQD3

Frequencies

GnomAD3 genomes
AF:
0.0167
AC:
2535
AN:
152144
Hom.:
73
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0587
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00491
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:
0.000162
Gnomad OTH
AF:
0.00814
GnomAD3 exomes
AF:
0.00389
AC:
977
AN:
251062
Hom.:
27
AF XY:
0.00286
AC XY:
389
AN XY:
135828
show subpopulations
Gnomad AFR exome
AF:
0.0561
Gnomad AMR exome
AF:
0.00150
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000653
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000114
Gnomad OTH exome
AF:
0.00114
GnomAD4 exome
AF:
0.00160
AC:
2339
AN:
1461868
Hom.:
53
Cov.:
32
AF XY:
0.00134
AC XY:
977
AN XY:
727234
show subpopulations
Gnomad4 AFR exome
AF:
0.0592
Gnomad4 AMR exome
AF:
0.00219
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000104
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000423
Gnomad4 OTH exome
AF:
0.00330
GnomAD4 genome
AF:
0.0167
AC:
2541
AN:
152260
Hom.:
74
Cov.:
32
AF XY:
0.0165
AC XY:
1228
AN XY:
74436
show subpopulations
Gnomad4 AFR
AF:
0.0587
Gnomad4 AMR
AF:
0.00484
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000162
Gnomad4 OTH
AF:
0.00806
Alfa
AF:
0.00610
Hom.:
11
Bravo
AF:
0.0183
Asia WGS
AF:
0.00375
AC:
13
AN:
3478
EpiCase
AF:
0.000164
EpiControl
AF:
0.000119

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:8
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:3
-
PreventionGenetics, part of Exact Sciences
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Mar 24, 2016
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. -

-
Genetic Services Laboratory, University of Chicago
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

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. -

Autosomal recessive limb-girdle muscular dystrophy type 2A Benign:3
Sep 16, 2020
Natera, Inc.
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Apr 28, 2017
Illumina Laboratory Services, Illumina
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

Feb 03, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Limb-girdle muscular dystrophy, recessive Benign:1
Jun 14, 2016
Illumina Laboratory Services, Illumina
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not provided Benign:1
-
Breakthrough Genomics, Breakthrough Genomics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.82
CADD
Benign
1.4
DANN
Benign
0.78

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs62642519; hg19: chr15-42652081; API