rs794727697

Positions:

• chr15-42389050-TGAA-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM4_Supporting PP5_Very_Strong

The NM_000070.3(CAPN3):​c.759_761delGAA​(p.Lys254del) variant causes a disruptive inframe deletion change. The variant allele was found at a frequency of 0.000062 in 1,613,988 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★★).

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000063 (0 hom.)
• Consequence: CAPN3 NM_000070.3 disruptive_inframe_deletion
• Clinical Significance: Pathogenic reviewed by expert panel P:12
• Conservation: PhyloP100: 5.60

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 Pathogenic. Variant got 11 ACMG points.

• PM1: In a helix (size 9) in uniprot entity CAN3_HUMAN there are 11 pathogenic changes around while only 0 benign (100%) in NM_000070.3
• PM4: Nonframeshift variant in NON repetitive region in NM_000070.3. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 15-42389050-TGAA-T is Pathogenic according to our data. Variant chr15-42389050-TGAA-T is described in ClinVar as [Pathogenic]. Clinvar id is 197624.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr15-42389050-TGAA-T is described in Lovd as [Pathogenic]. Variant chr15-42389050-TGAA-T is described in Lovd as [Pathogenic]. Variant chr15-42389050-TGAA-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CAPN3	NM_000070.3	c.759_761delGAA	p.Lys254del	disruptive_inframe_deletion	5/24	ENST00000397163.8	NP_000061.1
CAPN3	NM_024344.2	c.759_761delGAA	p.Lys254del	disruptive_inframe_deletion	5/23		NP_077320.1
CAPN3	NM_173087.2	c.759_761delGAA	p.Lys254del	disruptive_inframe_deletion	5/21		NP_775110.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CAPN3	ENST00000397163.8	c.759_761delGAA	p.Lys254del	disruptive_inframe_deletion	5/24	1	NM_000070.3	ENSP00000380349.3
ENSG00000258461	ENST00000495723.1	n.*555_*557delGAA		non_coding_transcript_exon_variant	9/26	2		ENSP00000492063.1
ENSG00000258461	ENST00000495723	n.*555_*557delGAA		3_prime_UTR_variant	9/23	2		ENSP00000492063.1

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152106 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000398 AC: 10 AN: 251418 Hom.: 0 AF XY: 0.0000515 AC XY: 7 AN XY: 135870

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000440

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000629 AC: 92 AN: 1461882 Hom.: 0 AF XY: 0.0000688 AC XY: 50 AN XY: 727246

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000755

Gnomad4 OTH exome AF: 0.0000828

GnomAD4 genome AF: 0.0000526 AC: 8 AN: 152106 Hom.: 0 Cov.: 32 AF XY: 0.0000673 AC XY: 5 AN XY: 74306

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000529

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:12

Revision: reviewed by expert panel

Submissions by phenotype

not provided Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 28, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Oct 27, 2020	The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant is statistically more frequent in affected individuals than in the general population and/or healthy controls. In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Oct 26, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 25, 2023	In-frame deletion of 1 amino acid in a non-repeat region predicted to critically alter the protein; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 22622166, 20694146, 34720847, 26810512, 16141003, 10330340, 28300015, 12461690, 27447704, 16344536, 18334579, 18563459, 30564623, 30919934, 31980526, 33741228, 32528171, 18055493) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2023	CAPN3: PM3:Very Strong, PM2, PM4:Supporting -

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

Pathogenic, no assertion criteria provided	clinical testing	Counsyl	Jul 28, 2017	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	May 06, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 03, 2024	This variant, c.759_761del, results in the deletion of 1 amino acid(s) of the CAPN3 protein (p.Lys254del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs760168012, gnomAD 0.01%). This variant has been observed in individual(s) with autosomal recessive limb-girdle muscular dystrophy (PMID: 10330340, 16141003, 18055493, 18334579, 18563459, 20694146, 22622166). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 197624). For these reasons, this variant has been classified as Pathogenic. -

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

Likely pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 23, 2024

- -

Autosomal recessive limb-girdle muscular dystrophy type 2A;C4748295:Muscular dystrophy, limb-girdle, autosomal dominant 4 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 29, 2024

- -

Autosomal recessive limb-girdle muscular dystrophy Pathogenic:1

Pathogenic, reviewed by expert panel

curation

ClinGen Limb Girdle Muscular Dystrophy Variant Curation Expert Panel, ClinGen

Jan 09, 2025

The NM_000070.3: c.759_761del variant in CAPN3, which is also known as c.756_758del, is predicted to cause a change in the length of the protein due to an in-frame deletion of one amino acid in a non-repeat region, p.(Lys254del) (PM4). This variant has been detected in at least 11 unrelated individuals with limb girdle muscular dystrophy (PMID: 26886200, 10330340, 16141003, 18055493, 30564623, 12461690, 35731190), including in a homozygous state in one case (0.5 pts; PMID: 18055493), confirmed in trans with a pathogenic variant in three cases (c.1468C>T p.(Arg490Trp), 1.0 pt, PMID: 12461690; c.1746-20C>G, 2.0 pts, PMID: 35731190), and in unknown phase with a pathogenic variant in one case (c.1468C>T p.(Arg490Trp), 0.5 pts, PMID: 18055493) (PM3_Very Strong). At least one patient with this variant displayed progressive limb girdle muscle weakness or a clinical suspicion of LGMD (PP4). The filtering allele frequency of the variant is 0.0001933 for European (non-Finnish) genome alleles in gnomAD v3.1.2 (the upper threshold of the 95% CI of 7/68016), which is greater than the LGMD VCEP threshold (<0.0001) for PM2_Supporting (criterion not met). In summary, this variant meets the criteria to be classified as Pathogenic 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; 01/09/2025): PM4, PM3_Very Strong, PP4. -

See cases Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Feb 03, 2022

ACMG classification criteria: PS3, PS4, PM4 -

Computational scores

Source: dbNSFP v4.3

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: rs794727697; hg19: chr15-42681248;