15-42409372-G-T

Position:

• chr15-42409372-G-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.1984G>T​(p.Ala662Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000237 in 1,614,126 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00025 (1 hom.)
• Consequence: CAPN3 NM_000070.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:9
• Conservation: PhyloP100: 9.97

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]

ENSG00000258461 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM1: In a helix (size 8) in uniprot entity CAN3_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_000070.3
• BP4: Computational evidence support a benign effect (MetaRNN=0.15651599).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CAPN3	NM_000070.3	c.1984G>T	p.Ala662Ser	missense_variant	17/24	ENST00000397163.8	NP_000061.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CAPN3	ENST00000397163.8	c.1984G>T	p.Ala662Ser	missense_variant	17/24	1	NM_000070.3	ENSP00000380349.3
CAPN3	ENST00000673886	c.-12G>T		5_prime_UTR_variant	4/11			ENSP00000501155.1
CAPN3	ENST00000673928	c.-12G>T		5_prime_UTR_variant	4/11			ENSP00000501099.1
CAPN3	ENST00000674146	c.-12G>T		5_prime_UTR_variant	5/12			ENSP00000501175.1
CAPN3	ENST00000674149	c.-12G>T		5_prime_UTR_variant	4/11			ENSP00000501112.1
CAPN3	ENST00000673743	c.-109G>T		5_prime_UTR_variant	4/11			ENSP00000500989.1
ENSG00000258461	ENST00000495723.1	n.*2420G>T		non_coding_transcript_exon_variant	19/26	2		ENSP00000492063.1
ENSG00000258461	ENST00000495723.1	n.*2420G>T		3_prime_UTR_variant	19/26	2		ENSP00000492063.1

Frequencies

GnomAD3 genomes AF: 0.000138 AC: 21 AN: 152208 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000322 AC: 81 AN: 251350 Hom.: 0 AF XY: 0.000427 AC XY: 58 AN XY: 135844

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.000595

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00176

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000114

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000247 AC: 361 AN: 1461800 Hom.: 1 Cov.: 31 AF XY: 0.000314 AC XY: 228 AN XY: 727208

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000268

Gnomad4 ASJ exome AF: 0.000536

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00194

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000129

Gnomad4 OTH exome AF: 0.000298

GnomAD4 genome AF: 0.000138 AC: 21 AN: 152326 Hom.: 0 Cov.: 32 AF XY: 0.000148 AC XY: 11 AN XY: 74498

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000206

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000179 Hom.: 0

Bravo AF: 0.000110

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000329 AC: 40

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.000178

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal recessive limb-girdle muscular dystrophy type 2A Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 28, 2022	This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 662 of the CAPN3 protein (p.Ala662Ser). This variant is present in population databases (rs187054121, gnomAD 0.2%). This missense change has been observed in individual(s) with limb-girdle muscular dystrophy (LGMD) (PMID: 1691480, 16141003, 18854869). ClinVar contains an entry for this variant (Variation ID: 468646). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt CAPN3 protein function. 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Pars Genome Lab	May 18, 2021	- -
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). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

not provided Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jul 19, 2019	Reported previously in a patient with late-onset limb-girdle muscular dystrophy who did not have a second identifiable pathogenic CAPN3 variant (Fanin et al., 2007); Reported previously in a patient with limb-girdle muscular dystrophy who harbored another CAPN3 missense variant and results of a functional test showed this patient had loss of calpain-3 of autolytic activity (Fanin et al., 2009); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 18854869, 1691480, 25898921, 16971480, 16141003, 25525159) -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 08, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 08, 2024	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Dec 12, 2023

Variant summary: CAPN3 c.1984G>T (p.Ala662Ser) results in a conservative amino acid change located in the penta-EF-hand (PEF) domain (IPR029531) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00023 in 1,607,152 control chromosomes, predominantly at a frequency of 0.0019 within the South Asian subpopulation in the gnomAD database, including 1 homozygote. This frequency is not significantly higher than the estimated maximum expected for a pathogenic variant in CAPN3 causing Limb-Girdle Muscular Dystrophy, Autosomal Recessive (0.0032), allowing no conclusion about variant significance. The variant, c.1984G>T, has been reported in the literature in heterozygous state (i.e. without identifying a second variant) in individuals affected with Limb-Girdle Muscular Dystrophy (e.g. Piluso_2005, Fanin_2007, Nallamilli_2018); where muscle biopsy specimen from one of these patients demonstrated loss of calpain-3 autolytic activity (Fanin_2007). These reports do not provide unequivocal conclusions about association of the variant with Limb-Girdle Muscular Dystrophy, Autosomal Recessive. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 16141003, 16971480, 30564623). Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Autosomal recessive limb-girdle muscular dystrophy type 2A;C4748295:Muscular dystrophy, limb-girdle, autosomal dominant 4 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Sep 01, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Pathogenic	0.43
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.027	T;.;.;T;.;.;.
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D;D;D;D;D;D;D
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.16	T;T;T;T;T;T;T
MetaSVM	Uncertain	0.67	D
MutationAssessor	Benign	1.9	.;.;.;L;.;.;.
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-2.0	.;N;N;N;N;N;N
REVEL	Pathogenic	0.77
Sift	Benign	0.082	.;T;T;T;T;T;T
Sift4G	Benign	0.14	T;T;T;T;T;T;T
Polyphen		0.42, 0.057, 0.30	.;B;B;B;.;.;.
Vest4		0.89
MVP		0.95
MPC		0.31
ClinPred		0.088	T
GERP RS		5.0
Varity_R		0.64
gMVP		0.53

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: rs187054121; hg19: chr15-42701570;