rs1801496

Positions:

• chr15-42359901-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.96T>C​(p.Thr32Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0872 in 1,614,140 control chromosomes in the GnomAD database, including 7,349 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.097 (840 hom., cov: 32)
  • Exomes 𝑓: 0.086 (6509 hom.)
• Consequence: CAPN3 NM_000070.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: -4.53

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=-0.96).
• BP6: Variant 15-42359901-T-C is Benign according to our data. Variant chr15-42359901-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 92422.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-42359901-T-C is described in Lovd as [Benign]. Variant chr15-42359901-T-C is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-4.53 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.175 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CAPN3	NM_000070.3	c.96T>C	p.Thr32Thr	synonymous_variant	1/24	ENST00000397163.8	NP_000061.1
CAPN3	NM_024344.2	c.96T>C	p.Thr32Thr	synonymous_variant	1/23		NP_077320.1
CAPN3	NM_173087.2	c.96T>C	p.Thr32Thr	synonymous_variant	1/21		NP_775110.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CAPN3	ENST00000397163.8	c.96T>C	p.Thr32Thr	synonymous_variant	1/24	1	NM_000070.3	ENSP00000380349.3
ENSG00000258461	ENST00000495723.1	n.*105+5448T>C		intron_variant		2		ENSP00000492063.1

Frequencies

GnomAD3 genomes AF: 0.0966 AC: 14703 AN: 152162 Hom.: 830 Cov.: 32

Gnomad AFR AF: 0.133

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.0714

Gnomad ASJ AF: 0.136

Gnomad EAS AF: 0.00308

Gnomad SAS AF: 0.185

Gnomad FIN AF: 0.100

Gnomad MID AF: 0.0981

Gnomad NFE AF: 0.0801

Gnomad OTH AF: 0.0946

GnomAD3 exomes AF: 0.0911 AC: 22885 AN: 251334 Hom.: 1431 AF XY: 0.0985 AC XY: 13389 AN XY: 135868

Gnomad AFR exome AF: 0.135

Gnomad AMR exome AF: 0.0454

Gnomad ASJ exome AF: 0.127

Gnomad EAS exome AF: 0.00174

Gnomad SAS exome AF: 0.199

Gnomad FIN exome AF: 0.0983

Gnomad NFE exome AF: 0.0794

Gnomad OTH exome AF: 0.0939

GnomAD4 exome AF: 0.0862 AC: 126073 AN: 1461860 Hom.: 6509 Cov.: 33 AF XY: 0.0901 AC XY: 65555 AN XY: 727230

Gnomad4 AFR exome AF: 0.133

Gnomad4 AMR exome AF: 0.0490

Gnomad4 ASJ exome AF: 0.125

Gnomad4 EAS exome AF: 0.00146

Gnomad4 SAS exome AF: 0.197

Gnomad4 FIN exome AF: 0.101

Gnomad4 NFE exome AF: 0.0785

Gnomad4 OTH exome AF: 0.0936

GnomAD4 genome AF: 0.0968 AC: 14748 AN: 152280 Hom.: 840 Cov.: 32 AF XY: 0.0980 AC XY: 7296 AN XY: 74452

Gnomad4 AFR AF: 0.133

Gnomad4 AMR AF: 0.0713

Gnomad4 ASJ AF: 0.136

Gnomad4 EAS AF: 0.00308

Gnomad4 SAS AF: 0.185

Gnomad4 FIN AF: 0.100

Gnomad4 NFE AF: 0.0801

Gnomad4 OTH AF: 0.0931

Alfa AF: 0.0878 Hom.: 342

Bravo AF: 0.0933

Asia WGS AF: 0.0890 AC: 308 AN: 3478

EpiCase AF: 0.0852

EpiControl AF: 0.0855

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:15

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:7

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 07, 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, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 15, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 01, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 13, 2015	p.Thr32Thr in exon 1 of CAPN3: This variant is not expected to have clinical sig nificance because it does not alter an amino acid residue and is not located wit hin the splice consensus sequence. It has been identified in 13.9% (611/4406) of African American chromosomes from a broad population by the NHLBI Exome Sequenc ing Project (http://evs.gs.washington.edu/EVS; dbSNP rs1801496). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

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

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 01, 2021	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
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 28, 2017	- -

Muscular dystrophy, limb-girdle, autosomal dominant 4 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 01, 2021

- -

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	-0.96
CADD	Benign	0.058
DANN	Benign	0.25

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: rs1801496; hg19: chr15-42652099;