rs115311625

chr15-42410952-G-Achr15-42410952-G-C

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000070.3(CAPN3):c.2332G>A(p.Asp778Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00158 in 1,614,140 control chromosomes in the GnomAD database, including 37 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0082 (26 hom., cov: 31)
  • Exomes 𝑓: 0.00089 (11 hom.)
• Consequence: CAPN3 NM_000070.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1 B:10
• Conservation: PhyloP100: 8.09

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 Benign. Variant got -18 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_000070.3
• BP4: Computational evidence support a benign effect (MetaRNN=0.017415226).
• BP6: Variant 15-42410952-G-A is Benign according to our data. Variant chr15-42410952-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 92413.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-42410952-G-A is described in Lovd as [Likely_benign]. Variant chr15-42410952-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00822 (1252/152296) while in subpopulation AFR AF= 0.0287 (1195/41566). AF 95% confidence interval is 0.0274. There are 26 homozygotes in gnomad4. There are 580 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 26 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CAPN3	NM_000070.3	c.2332G>A	p.Asp778Asn	missense_variant	22/24	ENST00000397163.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CAPN3	ENST00000397163.8	c.2332G>A	p.Asp778Asn	missense_variant	22/24	1	NM_000070.3	P2

Frequencies

GnomAD3 genomes AF: 0.00822 AC: 1251 AN: 152178 Hom.: 26 Cov.: 31

Gnomad AFR AF: 0.0288

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00249

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: 0.0000735

Gnomad OTH AF: 0.00669

GnomAD3 exomes AF: 0.00222 AC: 557 AN: 251396 Hom.: 8 AF XY: 0.00154 AC XY: 209 AN XY: 135856

Gnomad AFR exome AF: 0.0307

Gnomad AMR exome AF: 0.00107

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: 0.0000968

Gnomad OTH exome AF: 0.00130

GnomAD4 exome AF: 0.000889 AC: 1299 AN: 1461844 Hom.: 11 Cov.: 32 AF XY: 0.000759 AC XY: 552 AN XY: 727232

Gnomad4 AFR exome AF: 0.0313

Gnomad4 AMR exome AF: 0.00132

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.0000782

Gnomad4 OTH exome AF: 0.00156

GnomAD4 genome AF: 0.00822 AC: 1252 AN: 152296 Hom.: 26 Cov.: 31 AF XY: 0.00779 AC XY: 580 AN XY: 74474

Gnomad4 AFR AF: 0.0287

Gnomad4 AMR AF: 0.00248

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00662

Alfa AF: 0.00151 Hom.: 5

Bravo AF: 0.00942

ESP6500AA AF: 0.0261 AC: 115

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00282 AC: 342

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:1 Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal recessive limb-girdle muscular dystrophy type 2A Pathogenic:1 Benign:4

Likely benign, 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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Pathogenic, flagged submission	clinical testing	Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	Aug 16, 2017	This mutation has been reported in 1000 genomes and ExAC databases with minor allele frequency of 0.9% and 0.28%. The in silico prediction of this variant is damaging by Mutation Taster2. -
Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 11, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Counsyl	Sep 12, 2017	- -

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 28, 2016	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. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 23, 2012	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 13, 2023	Variant summary: CAPN3 c.2332G>A (p.Asp778Asn) results in a conservative amino acid change located in the penta-EF-hand domain (IPR029531) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0022 in 251396 control chromosomes, predominantly at a frequency of 0.031 within the African or African-American subpopulation in the gnomAD database, including 7 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 10-fold of the estimated maximal expected allele frequency for a pathogenic variant in CAPN3 causing an autosomal recessive Limb-Girdle Muscular Dystrophy phenotype (0.0032), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.2332G>A has been reported in the literature in the compound heterozygous state in one individual affected with Limb-Girdle Muscular Dystrophy (Pathak_2021). This report does not provide unequivocal conclusions about association of the variant with Limb-Girdle Muscular Dystrophy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven submitters have provided clinical-significance assessments for this variant to ClinVar after 2014. The majority classified the variant as benign (n=3)/likely benign (n=3) and one classified it as pathogenic. Based on the evidence outlined above, the variant was classified as benign. -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Oct 29, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.12
Cadd	Pathogenic	27
Dann	Uncertain	1.0
DEOGEN2	Benign	0.065	T;.;.;T;.;.;.;.;.;.;.
Eigen	Benign	0.14
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.90	D;D;D;D;D;D;.;D;.;D;.
MetaRNN	Benign	0.017	T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.017	T
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.64	T
REVEL	Uncertain	0.44
Sift4G	Benign	0.20	T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.022, 0.010, 0.023	.;B;B;B;.;.;.;.;.;.;.
Vest4		0.46
MVP		0.93
MPC		0.14
ClinPred		0.059	T
GERP RS		4.4
Varity_R		0.49
gMVP		0.68

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs115311625; hg19: chr15-42703150; COSMIC: COSV99028101; COSMIC: COSV99028101;