rs201512120

Positions:

• chr15-42405964-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4 BP7 BS1

This summary comes from the ClinGen Evidence Repository: The NM_000070.3: c.1800+21C>T variant in CAPN3 is an intronic variant that does not occur in a splice region (+7/-21). The filtering allele frequency for this variant is 0.002152 for the European (non-Finnish) population in gnomAD v4.1.0 (the lower threshold of the 95% CI of 2461/1105660 exome chromosomes), which is greater than the ClinGen LGMD VCEP threshold of 0.001 for BS1, and therefore meets this criterion (BS1). The SpliceAI prediction score for this variant is 0.01, which is less than the VCEP threshold of 0.05 (BP4, BP7). In summary, this variant meets the criteria to be classified as Likely Benign for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the LGMD VCEP (LGMD VCEP specifications version 1.0.0; 01/09/2025): BS1, BP4, BP7. LINK:https://erepo.genome.network/evrepo/ui/classification/CA7511545/MONDO:0015152/187

• Frequency:
  • Genomes: 𝑓 0.0015 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0018 (6 hom.)
• Consequence: CAPN3 NM_000070.3 intron
• Clinical Significance: Likely benign reviewed by expert panel B:1
• Conservation: PhyloP100: 0.110

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 Likely_benign. Variant got -6 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.
• BS1: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CAPN3	NM_000070.3	c.1800+21C>T		intron_variant		ENST00000397163.8	NP_000061.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CAPN3	ENST00000397163.8	c.1800+21C>T		intron_variant		1	NM_000070.3	ENSP00000380349.3
CAPN3	ENST00000673886.1	c.-928-733C>T		intron_variant				ENSP00000501155.1
CAPN3	ENST00000673928.1	c.-340+1009C>T		intron_variant				ENSP00000501099.1
CAPN3	ENST00000674146.1	c.-524+21C>T		intron_variant				ENSP00000501175.1
CAPN3	ENST00000674149.1	c.-524+1009C>T		intron_variant				ENSP00000501112.1
CAPN3	ENST00000673743.1	c.-437+1009C>T		intron_variant				ENSP00000500989.1
ENSG00000258461	ENST00000495723.1	n.*2236+2187C>T		intron_variant		2		ENSP00000492063.1

Frequencies

GnomAD3 genomes AF: 0.00150 AC: 228 AN: 152128 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000579

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.00282

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00223

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.00135 AC: 337 AN: 249142 Hom.: 0 AF XY: 0.00130 AC XY: 176 AN XY: 135144

Gnomad AFR exome AF: 0.000323

Gnomad AMR exome AF: 0.00209

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000445

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00217

Gnomad OTH exome AF: 0.00116

GnomAD4 exome AF: 0.00184 AC: 2673 AN: 1454882 Hom.: 6 Cov.: 28 AF XY: 0.00182 AC XY: 1319 AN XY: 724236

Gnomad4 AFR exome AF: 0.000330

Gnomad4 AMR exome AF: 0.00199

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.00223

Gnomad4 OTH exome AF: 0.00176

GnomAD4 genome AF: 0.00150 AC: 228 AN: 152246 Hom.: 0 Cov.: 32 AF XY: 0.00124 AC XY: 92 AN XY: 74446

Gnomad4 AFR AF: 0.000578

Gnomad4 AMR AF: 0.00281

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000387

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00223

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00137 Hom.: 0

Bravo AF: 0.00156

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: reviewed by expert panel

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Nov 05, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	1.4
DANN	Benign	0.51

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs201512120; hg19: chr15-42698162;