rs138867099

Positions:

• chr15-42360037-C-A
• chr15-42360037-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM1 BP4_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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:2
• 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]

ACMG classification

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: 48 AN: 152204 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000981

Gnomad ASJ AF: 0.00375

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000385 AC: 96 AN: 249514 Hom.: 0 AF XY: 0.000474 AC XY: 64 AN XY: 135008

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000838

Gnomad ASJ exome AF: 0.00298

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000224

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.000227 AC: 332 AN: 1461868 Hom.: 0 Cov.: 32 AF XY: 0.000259 AC XY: 188 AN XY: 727230

Gnomad4 AFR exome AF: 0.000209

Gnomad4 AMR exome AF: 0.000760

Gnomad4 ASJ exome AF: 0.00283

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000163

Gnomad4 OTH exome AF: 0.000298

GnomAD4 genome AF: 0.000315 AC: 48 AN: 152322 Hom.: 0 Cov.: 32 AF XY: 0.000228 AC XY: 17 AN XY: 74480

Gnomad4 AFR AF: 0.000241

Gnomad4 AMR AF: 0.000980

Gnomad4 ASJ AF: 0.00375

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000264 Hom.: 0

Bravo AF: 0.000419

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000371 AC: 45

EpiCase AF: 0.000491

EpiControl AF: 0.000533

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Autosomal recessive limb-girdle muscular dystrophy type 2A Uncertain:3 Benign: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:1 Benign: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: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Uncertain	0.061	T
BayesDel_noAF	Pathogenic	0.23
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.32	T;.;.;D
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.73	T;T;T;T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.14	T;T;T;T
MetaSVM	Uncertain	0.70	D
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.54	T
PROVEAN	Uncertain	-3.7	D;D;D;D
REVEL	Pathogenic	0.65
Sift	Benign	0.033	D;D;D;D
Sift4G	Uncertain	0.018	D;D;D;D
Polyphen		0.56, 0.42, 0.61	.;P;B;P
Vest4		0.63
MVP		0.96
MPC		0.48
ClinPred		0.073	T
GERP RS		6.0
Varity_R		0.61
gMVP		0.74

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

Other links and lift over

dbSNP: rs138867099; hg19: chr15-42652235;