rs2241827

Variant names:

• chr15-42402746-T-C
• rs2241827
• NM_000070.3:c.1537-48T>C

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP7 BP4 BA1

This summary comes from the ClinGen Evidence Repository: The NM_000070.3: c.1537-48T>C variant in CAPN3 is an intronic variant. The filtering allele frequency for this variant is 0.9344 in gnomAD v4.1.0 (the lower threshold of the 95% CI of 31266/33150 African/African American exome chromosomes), which is greater than the ClinGen LGMD VCEP threshold ≥0.003 for BA1 (BA1). The SpliceAI prediction of 0.00 indicates no splicing impact and does not exceed the LGMD VCEP threshold of ≤0.05 (BP4). This variant is also not in a splice region (BP7). In summary, this variant meets the criteria to be classified as Benign for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 03/14/2025): BA1, BP4, BP7. LINK:https://erepo.genome.network/evrepo/ui/classification/CA145717/MONDO:0015152/187

• Frequency:
  • Genomes: 𝑓 0.76 (44598 hom., cov: 32)
  • Exomes 𝑓: 0.70 (353734 hom.)
• Consequence: CAPN3 NM_000070.3 intron
• Clinical Significance: Benign reviewed by expert panel B:7
• Conservation: PhyloP100: -2.08

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 -10 ACMG points.

• BP4: For more information check the summary or visit ClinGen Evidence Repository.
• BP7: For more information check the summary or visit ClinGen Evidence Repository.
• BA1: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CAPN3	NM_000070.3	c.1537-48T>C		intron_variant	Intron 12 of 23	ENST00000397163.8	NP_000061.1
CAPN3	NM_024344.2	c.1537-48T>C		intron_variant	Intron 12 of 22		NP_077320.1
CAPN3	NM_173087.2	c.1393-48T>C		intron_variant	Intron 11 of 20		NP_775110.1
CAPN3	NM_173088.2	c.1-48T>C		intron_variant	Intron 1 of 12		NP_775111.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CAPN3	ENST00000397163.8	c.1537-48T>C		intron_variant	Intron 12 of 23	1	NM_000070.3	ENSP00000380349.3
ENSG00000258461	ENST00000495723.1	n.*1943T>C		non_coding_transcript_exon_variant	Exon 16 of 26	2		ENSP00000492063.1
ENSG00000258461	ENST00000495723.1	n.*1943T>C		3_prime_UTR_variant	Exon 16 of 26	2		ENSP00000492063.1

Frequencies

GnomAD3 genomes AF: 0.755 AC: 114785 AN: 151966 Hom.: 44544 Cov.: 32

Gnomad AFR AF: 0.934

Gnomad AMI AF: 0.785

Gnomad AMR AF: 0.705

Gnomad ASJ AF: 0.773

Gnomad EAS AF: 0.427

Gnomad SAS AF: 0.696

Gnomad FIN AF: 0.645

Gnomad MID AF: 0.744

Gnomad NFE AF: 0.703

Gnomad OTH AF: 0.757

GnomAD3 exomes AF: 0.682 AC: 168544 AN: 247040 Hom.: 58932 AF XY: 0.687 AC XY: 92014 AN XY: 134008

Gnomad AFR exome AF: 0.935

Gnomad AMR exome AF: 0.608

Gnomad ASJ exome AF: 0.765

Gnomad EAS exome AF: 0.423

Gnomad SAS exome AF: 0.704

Gnomad FIN exome AF: 0.633

Gnomad NFE exome AF: 0.706

Gnomad OTH exome AF: 0.700

GnomAD4 exome AF: 0.696 AC: 1006273 AN: 1444820 Hom.: 353734 Cov.: 28 AF XY: 0.697 AC XY: 502013 AN XY: 719856

Gnomad4 AFR exome AF: 0.943

Gnomad4 AMR exome AF: 0.625

Gnomad4 ASJ exome AF: 0.767

Gnomad4 EAS exome AF: 0.413

Gnomad4 SAS exome AF: 0.707

Gnomad4 FIN exome AF: 0.633

Gnomad4 NFE exome AF: 0.702

Gnomad4 OTH exome AF: 0.710

GnomAD4 genome AF: 0.755 AC: 114895 AN: 152084 Hom.: 44598 Cov.: 32 AF XY: 0.750 AC XY: 55712 AN XY: 74332

Gnomad4 AFR AF: 0.935

Gnomad4 AMR AF: 0.704

Gnomad4 ASJ AF: 0.773

Gnomad4 EAS AF: 0.428

Gnomad4 SAS AF: 0.696

Gnomad4 FIN AF: 0.645

Gnomad4 NFE AF: 0.703

Gnomad4 OTH AF: 0.751

Alfa AF: 0.722 Hom.: 43925

Bravo AF: 0.766

Asia WGS AF: 0.567 AC: 1972 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: reviewed by expert panel

Submissions by phenotype

not specified Benign:2

Aug 24, 2012

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 14, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

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

Jun 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal recessive limb-girdle muscular dystrophy Benign:1

Mar 14, 2025

ClinGen Limb Girdle Muscular Dystrophy Variant Curation Expert Panel, ClinGen

Significance: Benign

Review Status: reviewed by expert panel

Collection Method: curation

The NM_000070.3: c.1537-48T>C variant in CAPN3 is an intronic variant. The filtering allele frequency for this variant is 0.9344 in gnomAD v4.1.0 (the lower threshold of the 95% CI of 31266/33150 African/African American exome chromosomes), which is greater than the ClinGen LGMD VCEP threshold ≥0.003 for BA1 (BA1). The SpliceAI prediction of 0.00 indicates no splicing impact and does not exceed the LGMD VCEP threshold of ≤0.05 (BP4). This variant is also not in a splice region (BP7). In summary, this variant meets the criteria to be classified as Benign for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 03/14/2025): BA1, BP4, BP7. -

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

Jun 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.50
DANN	Benign	0.34
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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: rs2241827; hg19: chr15-42694944; COSMIC: COSV58823002; COSMIC: COSV58823002;