rs1801449

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000070.3(CAPN3):​c.706G>A​(p.Ala236Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0836 in 1,613,710 control chromosomes in the GnomAD database, including 19,097 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.22 ( 8667 hom., cov: 31)
Exomes 𝑓: 0.069 ( 10430 hom. )

Consequence

CAPN3
NM_000070.3 missense

Scores

2
16

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:17

Conservation

PhyloP100: 5.24
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 -20 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=3.6192458E-5).
BP6
Variant 15-42389001-G-A is Benign according to our data. Variant chr15-42389001-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 92420.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-42389001-G-A is described in Lovd as [Benign]. Variant chr15-42389001-G-A is described in Lovd as [Likely_benign]. Variant chr15-42389001-G-A is described in Lovd as [Pathogenic]. Variant chr15-42389001-G-A is described in Lovd as [Pathogenic]. Variant chr15-42389001-G-A is described in Lovd as [Likely_pathogenic]. Variant chr15-42389001-G-A is described in Lovd as [Likely_pathogenic].
BA1
GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.624 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CAPN3NM_000070.3 linkc.706G>A p.Ala236Thr missense_variant Exon 5 of 24 ENST00000397163.8 NP_000061.1 P20807-1
CAPN3NM_024344.2 linkc.706G>A p.Ala236Thr missense_variant Exon 5 of 23 NP_077320.1 P20807-3
CAPN3NM_173087.2 linkc.706G>A p.Ala236Thr missense_variant Exon 5 of 21 NP_775110.1 P20807-2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CAPN3ENST00000397163.8 linkc.706G>A p.Ala236Thr missense_variant Exon 5 of 24 1 NM_000070.3 ENSP00000380349.3 P20807-1
ENSG00000258461ENST00000495723.1 linkn.*502G>A non_coding_transcript_exon_variant Exon 9 of 26 2 ENSP00000492063.1 A0A1W2PQD3
ENSG00000258461ENST00000495723.1 linkn.*502G>A 3_prime_UTR_variant Exon 9 of 26 2 ENSP00000492063.1 A0A1W2PQD3

Frequencies

GnomAD3 genomes
AF:
0.222
AC:
33668
AN:
151864
Hom.:
8632
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.630
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0989
Gnomad ASJ
AF:
0.104
Gnomad EAS
AF:
0.117
Gnomad SAS
AF:
0.135
Gnomad FIN
AF:
0.0960
Gnomad MID
AF:
0.0823
Gnomad NFE
AF:
0.0465
Gnomad OTH
AF:
0.169
GnomAD3 exomes
AF:
0.113
AC:
28526
AN:
251464
Hom.:
4356
AF XY:
0.106
AC XY:
14383
AN XY:
135906
show subpopulations
Gnomad AFR exome
AF:
0.643
Gnomad AMR exome
AF:
0.0761
Gnomad ASJ exome
AF:
0.105
Gnomad EAS exome
AF:
0.128
Gnomad SAS exome
AF:
0.140
Gnomad FIN exome
AF:
0.0946
Gnomad NFE exome
AF:
0.0454
Gnomad OTH exome
AF:
0.0836
GnomAD4 exome
AF:
0.0692
AC:
101133
AN:
1461728
Hom.:
10430
Cov.:
32
AF XY:
0.0698
AC XY:
50733
AN XY:
727158
show subpopulations
Gnomad4 AFR exome
AF:
0.651
Gnomad4 AMR exome
AF:
0.0779
Gnomad4 ASJ exome
AF:
0.106
Gnomad4 EAS exome
AF:
0.112
Gnomad4 SAS exome
AF:
0.138
Gnomad4 FIN exome
AF:
0.0950
Gnomad4 NFE exome
AF:
0.0404
Gnomad4 OTH exome
AF:
0.101
GnomAD4 genome
AF:
0.222
AC:
33763
AN:
151982
Hom.:
8667
Cov.:
31
AF XY:
0.219
AC XY:
16236
AN XY:
74296
show subpopulations
Gnomad4 AFR
AF:
0.630
Gnomad4 AMR
AF:
0.0986
Gnomad4 ASJ
AF:
0.104
Gnomad4 EAS
AF:
0.118
Gnomad4 SAS
AF:
0.136
Gnomad4 FIN
AF:
0.0960
Gnomad4 NFE
AF:
0.0465
Gnomad4 OTH
AF:
0.167
Alfa
AF:
0.0794
Hom.:
4028
Bravo
AF:
0.241
TwinsUK
AF:
0.0418
AC:
155
ALSPAC
AF:
0.0376
AC:
145
ESP6500AA
AF:
0.621
AC:
2737
ESP6500EA
AF:
0.0497
AC:
427
ExAC
AF:
0.124
AC:
15028
Asia WGS
AF:
0.143
AC:
497
AN:
3476
EpiCase
AF:
0.0481
EpiControl
AF:
0.0458

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:17
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:7
Dec 04, 2015
Eurofins Ntd Llc (ga)
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jan 14, 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. -

Oct 29, 2014
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

p.Ala236Thr in exon 5 of CAPN3: This variant is not expected to have clinical si gnificance because it has been identified in 62% (2737/4406) of African American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu /EVS/; dbSNP rs1801449). -

Dec 10, 2021
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Feb 10, 2016
PreventionGenetics, part of Exact Sciences
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
Clinical Genetics, Academic Medical Center
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Sep 10, 2013
Genetic Services Laboratory, University of Chicago
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Autosomal recessive limb-girdle muscular dystrophy type 2A Benign:6
Sep 16, 2020
Natera, Inc.
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Apr 27, 2017
Illumina Laboratory Services, Illumina
Significance: 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 was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Jun 10, 2021
Genome-Nilou Lab
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

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

- -

Oct 09, 2014
Genome Diagnostics Laboratory, University Medical Center Utrecht
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

May 28, 2019
Mendelics
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not provided Benign:2
Apr 28, 2017
Athena Diagnostics
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

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

- -

Muscular dystrophy, limb-girdle, autosomal dominant 4 Benign:1
Jun 10, 2021
Genome-Nilou Lab
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: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.054
BayesDel_addAF
Benign
-0.48
T
BayesDel_noAF
Benign
-0.32
CADD
Benign
18
DANN
Benign
0.88
DEOGEN2
Benign
0.060
T;.;.;T
Eigen
Benign
-0.55
Eigen_PC
Benign
-0.28
FATHMM_MKL
Benign
0.26
N
LIST_S2
Benign
0.52
T;T;T;T
MetaRNN
Benign
0.000036
T;T;T;T
MetaSVM
Benign
-0.96
T
MutationAssessor
Benign
-1.1
.;N;N;N
PrimateAI
Uncertain
0.73
T
PROVEAN
Benign
1.2
N;N;N;N
REVEL
Uncertain
0.35
Sift
Benign
0.87
T;T;T;T
Sift4G
Benign
1.0
T;T;T;T
Polyphen
0.0
.;B;B;B
Vest4
0.058
MPC
0.14
ClinPred
0.013
T
GERP RS
5.4
Varity_R
0.56
gMVP
0.51

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: rs1801449; hg19: chr15-42681199; COSMIC: COSV58820420; API