rs138867099
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM1BP4_Moderate
The NM_000070.3(CAPN3):c.232C>A(p.Pro78Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000235 in 1,614,190 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.00032 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00023 ( 0 hom. )
Consequence
CAPN3
NM_000070.3 missense
NM_000070.3 missense
Scores
2
10
6
Clinical Significance
Conservation
PhyloP100: 5.12
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 0 ACMG points.
PM1
?
In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_000070.3
BP4
?
Computational evidence support a benign effect (MetaRNN=0.13818789).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CAPN3 | NM_000070.3 | c.232C>A | p.Pro78Thr | missense_variant | 1/24 | ENST00000397163.8 | |
CAPN3 | NM_024344.2 | c.232C>A | p.Pro78Thr | missense_variant | 1/23 | ||
CAPN3 | NM_173087.2 | c.232C>A | p.Pro78Thr | missense_variant | 1/21 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CAPN3 | ENST00000397163.8 | c.232C>A | p.Pro78Thr | missense_variant | 1/24 | 1 | NM_000070.3 | P2 | |
CAPN3 | ENST00000357568.8 | c.232C>A | p.Pro78Thr | missense_variant | 1/23 | 1 | |||
CAPN3 | ENST00000349748.8 | c.232C>A | p.Pro78Thr | missense_variant | 1/21 | 1 | |||
CAPN3 | ENST00000318023.11 | c.232C>A | p.Pro78Thr | missense_variant | 1/23 | 5 | A2 |
Frequencies
GnomAD3 genomes ? AF: 0.000315 AC: 48AN: 152204Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000385 AC: 96AN: 249514Hom.: 0 AF XY: 0.000474 AC XY: 64AN XY: 135008
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GnomAD4 exome AF: 0.000227 AC: 332AN: 1461868Hom.: 0 Cov.: 32 AF XY: 0.000259 AC XY: 188AN XY: 727230
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GnomAD4 genome ? AF: 0.000315 AC: 48AN: 152322Hom.: 0 Cov.: 32 AF XY: 0.000228 AC XY: 17AN XY: 74480
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:4Benign:2
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Autosomal recessive limb-girdle muscular dystrophy type 2A Uncertain:3Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Jan 03, 2019 | This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | 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 did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 25, 2024 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Jan 07, 2020 | - - |
not provided Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Feb 14, 2018 | - - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Apr 20, 2021 | Reported previously in an individual undergoing next generation sequencing testing for myopathy, although further information was not provided on this individual (Di Fruscio et al., 2016); This variant is associated with the following publications: (PMID: 25898921) - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
T
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Benign
T;.;.;D
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T;T;T;T
M_CAP
Uncertain
D
MetaRNN
Benign
T;T;T;T
MetaSVM
Uncertain
D
MutationTaster
Benign
D;D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;D;D;D
REVEL
Pathogenic
Sift
Benign
D;D;D;D
Sift4G
Uncertain
D;D;D;D
Polyphen
0.56, 0.42, 0.61
.;P;B;P
Vest4
MVP
MPC
0.48
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at