15-42384491-C-T

Variant names:

• chr15-42384491-C-T
• rs117609395
• NM_000070.3:c.318C>T

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Moderate BP6_Very_Strong BP7 BS2

The NM_000070.3(CAPN3):​c.318C>T​(p.Cys106Cys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00573 in 1,612,482 control chromosomes in the GnomAD database, including 34 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0049 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0058 (34 hom.)
• Consequence: CAPN3 NM_000070.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -0.304

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 Benign. Variant got -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.31).
• BP6: Variant 15-42384491-C-T is Benign according to our data. Variant chr15-42384491-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 92416.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-42384491-C-T is described in Lovd as [Likely_benign]. Variant chr15-42384491-C-T is described in Lovd as [Benign]. Variant chr15-42384491-C-T is described in Lovd as [Pathogenic].
• BP7: Synonymous conserved (PhyloP=-0.304 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 34 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CAPN3	NM_000070.3	c.318C>T	p.Cys106Cys	synonymous_variant	Exon 2 of 24	ENST00000397163.8	NP_000061.1
CAPN3	NM_024344.2	c.318C>T	p.Cys106Cys	synonymous_variant	Exon 2 of 23		NP_077320.1
CAPN3	NM_173087.2	c.318C>T	p.Cys106Cys	synonymous_variant	Exon 2 of 21		NP_775110.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CAPN3	ENST00000397163.8	c.318C>T	p.Cys106Cys	synonymous_variant	Exon 2 of 24	1	NM_000070.3	ENSP00000380349.3
ENSG00000258461	ENST00000495723.1	n.*114C>T		non_coding_transcript_exon_variant	Exon 6 of 26	2		ENSP00000492063.1
ENSG00000258461	ENST00000495723.1	n.*114C>T		3_prime_UTR_variant	Exon 6 of 26	2		ENSP00000492063.1

Frequencies

GnomAD3 genomes AF: 0.00488 AC: 743 AN: 152136 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00138

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00628

Gnomad ASJ AF: 0.00404

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.00292

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00763

Gnomad OTH AF: 0.00766

GnomAD3 exomes AF: 0.00470 AC: 1182 AN: 251426 Hom.: 5 AF XY: 0.00475 AC XY: 646 AN XY: 135878

Gnomad AFR exome AF: 0.00111

Gnomad AMR exome AF: 0.00506

Gnomad ASJ exome AF: 0.00298

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00118

Gnomad FIN exome AF: 0.00282

Gnomad NFE exome AF: 0.00725

Gnomad OTH exome AF: 0.00603

GnomAD4 exome AF: 0.00582 AC: 8494 AN: 1460228 Hom.: 34 Cov.: 30 AF XY: 0.00570 AC XY: 4142 AN XY: 726566

Gnomad4 AFR exome AF: 0.000987

Gnomad4 AMR exome AF: 0.00532

Gnomad4 ASJ exome AF: 0.00283

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.00165

Gnomad4 FIN exome AF: 0.00275

Gnomad4 NFE exome AF: 0.00673

Gnomad4 OTH exome AF: 0.00585

GnomAD4 genome AF: 0.00487 AC: 742 AN: 152254 Hom.: 0 Cov.: 32 AF XY: 0.00450 AC XY: 335 AN XY: 74460

Gnomad4 AFR AF: 0.00137

Gnomad4 AMR AF: 0.00628

Gnomad4 ASJ AF: 0.00404

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00166

Gnomad4 FIN AF: 0.00292

Gnomad4 NFE AF: 0.00762

Gnomad4 OTH AF: 0.00758

Alfa AF: 0.00622 Hom.: 2

Bravo AF: 0.00533

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00971

EpiControl AF: 0.00877

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 13, 2015	p.Cys106Cys in exon 2 of CAPN3: This variant is not expected to have clinical si gnificance because it does not alter an amino acid residue and is not located wi thin the splice consensus sequence. It has been identified in 0.9% (78/8598) of European American chromosomes from a broad population by the NHLBI Exome Sequenc ing Project (http://evs.gs.washington.edu/EVS; dbSNP rs117609395). -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 21, 2014	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Oct 18, 2023	- -
Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

not provided Benign:4

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2020	This variant is associated with the following publications: (PMID: 10330340, 16141003) -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2025	CAPN3: BP4, BP7, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Autosomal recessive limb-girdle muscular dystrophy type 2A Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 03, 2025	- -
Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Dec 03, 2019	- -
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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.31
CADD	Benign	2.3
DANN	Benign	0.65

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: rs117609395; hg19: chr15-42676689; COSMIC: COSV58826257;