rs898013388

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_000070.3(CAPN3):ā€‹c.193C>Gā€‹(p.His65Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,878 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: not found (cov: 32)
Exomes š‘“: 0.0000027 ( 0 hom. )

Consequence

CAPN3
NM_000070.3 missense

Scores

5
4
10

Clinical Significance

Uncertain significance criteria provided, single submitter U:2

Conservation

PhyloP100: 2.17
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 Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
CAPN3NM_000070.3 linkc.193C>G p.His65Asp missense_variant 1/24 ENST00000397163.8 NP_000061.1 P20807-1
CAPN3NM_024344.2 linkc.193C>G p.His65Asp missense_variant 1/23 NP_077320.1 P20807-3
CAPN3NM_173087.2 linkc.193C>G p.His65Asp missense_variant 1/21 NP_775110.1 P20807-2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
CAPN3ENST00000397163.8 linkc.193C>G p.His65Asp missense_variant 1/241 NM_000070.3 ENSP00000380349.3 P20807-1
ENSG00000258461ENST00000495723.1 linkn.*105+5545C>G intron_variant 2 ENSP00000492063.1 A0A1W2PQD3

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.00000274
AC:
4
AN:
1461878
Hom.:
0
Cov.:
32
AF XY:
0.00000275
AC XY:
2
AN XY:
727236
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000270
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
Cov.:
32
Bravo
AF:
0.00000378

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Autosomal recessive limb-girdle muscular dystrophy type 2A Uncertain:2
Uncertain significance, no assertion criteria providedclinical testingNatera, Inc.Oct 07, 2020- -
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJun 27, 2022This sequence change replaces histidine, which is basic and polar, with aspartic acid, which is acidic and polar, at codon 65 of the CAPN3 protein (p.His65Asp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal recessive limb-girdle muscular dystrophy (LGMD) (PMID: 18055493). ClinVar contains an entry for this variant (Variation ID: 536515). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.67
BayesDel_addAF
Pathogenic
0.35
D
BayesDel_noAF
Pathogenic
0.26
CADD
Uncertain
23
DANN
Uncertain
0.99
DEOGEN2
Benign
0.028
T;.;.;T
Eigen
Benign
-0.11
Eigen_PC
Benign
0.084
FATHMM_MKL
Benign
0.58
D
LIST_S2
Benign
0.81
T;T;D;T
M_CAP
Benign
0.045
D
MetaRNN
Uncertain
0.68
D;D;D;D
MetaSVM
Uncertain
0.25
D
MutationAssessor
Benign
0.69
.;N;N;N
PrimateAI
Benign
0.47
T
PROVEAN
Benign
-2.0
N;N;N;N
REVEL
Uncertain
0.57
Sift
Pathogenic
0.0
D;D;D;D
Sift4G
Pathogenic
0.0010
D;D;D;D
Polyphen
0.070, 0.030, 0.042
.;B;B;B
Vest4
0.45
MutPred
0.85
Gain of ubiquitination at K67 (P = 0.0495);Gain of ubiquitination at K67 (P = 0.0495);Gain of ubiquitination at K67 (P = 0.0495);Gain of ubiquitination at K67 (P = 0.0495);
MVP
0.94
MPC
0.22
ClinPred
0.49
T
GERP RS
6.0
Varity_R
0.58
gMVP
0.89

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: rs898013388; hg19: chr15-42652196; API