rs17593

Positions:

• chr15-42387860-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000070.3(CAPN3):​c.606T>C​(p.Ser202Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0125 in 1,613,942 control chromosomes in the GnomAD database, including 1,130 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.050 (587 hom., cov: 32)
  • Exomes 𝑓: 0.0086 (543 hom.)
• Consequence: CAPN3 NM_000070.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -1.00

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BP6: Variant 15-42387860-T-C is Benign according to our data. Variant chr15-42387860-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 128573.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-42387860-T-C is described in Lovd as [Benign]. Variant chr15-42387860-T-C is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-1 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.159 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CAPN3	NM_000070.3	c.606T>C	p.Ser202Ser	synonymous_variant	4/24	ENST00000397163.8	NP_000061.1
CAPN3	NM_024344.2	c.606T>C	p.Ser202Ser	synonymous_variant	4/23		NP_077320.1
CAPN3	NM_173087.2	c.606T>C	p.Ser202Ser	synonymous_variant	4/21		NP_775110.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CAPN3	ENST00000397163.8	c.606T>C	p.Ser202Ser	synonymous_variant	4/24	1	NM_000070.3	ENSP00000380349.3
ENSG00000258461	ENST00000495723.1	n.*402T>C		non_coding_transcript_exon_variant	8/26	2		ENSP00000492063.1
ENSG00000258461	ENST00000495723.1	n.*402T>C		3_prime_UTR_variant	8/26	2		ENSP00000492063.1

Frequencies

GnomAD3 genomes AF: 0.0497 AC: 7548 AN: 151994 Hom.: 576 Cov.: 32

Gnomad AFR AF: 0.162

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0223

Gnomad ASJ AF: 0.0282

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0230

Gnomad FIN AF: 0.0000945

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.00310

Gnomad OTH AF: 0.0388

GnomAD3 exomes AF: 0.0180 AC: 4535 AN: 251450 Hom.: 264 AF XY: 0.0162 AC XY: 2204 AN XY: 135898

Gnomad AFR exome AF: 0.165

Gnomad AMR exome AF: 0.0110

Gnomad ASJ exome AF: 0.0289

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0221

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.00361

Gnomad OTH exome AF: 0.0140

GnomAD4 exome AF: 0.00856 AC: 12515 AN: 1461830 Hom.: 543 Cov.: 32 AF XY: 0.00871 AC XY: 6332 AN XY: 727204

Gnomad4 AFR exome AF: 0.166

Gnomad4 AMR exome AF: 0.0121

Gnomad4 ASJ exome AF: 0.0275

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.0226

Gnomad4 FIN exome AF: 0.000168

Gnomad4 NFE exome AF: 0.00227

Gnomad4 OTH exome AF: 0.0171

GnomAD4 genome AF: 0.0499 AC: 7591 AN: 152112 Hom.: 587 Cov.: 32 AF XY: 0.0479 AC XY: 3561 AN XY: 74360

Gnomad4 AFR AF: 0.162

Gnomad4 AMR AF: 0.0223

Gnomad4 ASJ AF: 0.0282

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0230

Gnomad4 FIN AF: 0.0000945

Gnomad4 NFE AF: 0.00310

Gnomad4 OTH AF: 0.0384

Alfa AF: 0.0165 Hom.: 188

Bravo AF: 0.0561

Asia WGS AF: 0.0200 AC: 70 AN: 3478

EpiCase AF: 0.00458

EpiControl AF: 0.00498

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

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. -
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	Dec 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 22, 2013	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 15, 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. -

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

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 29, 2017	- -

Limb-girdle muscular dystrophy, recessive Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	1.1
DANN	Benign	0.59

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: rs17593; hg19: chr15-42680058;