rs80338802

Variant names:

• chr15-42410926-G-A
• rs80338802
• NM_000070.3:c.2306G>A

Your query was ambiguous. Multiple possible variants found:

• chr15-42410926-G-A
• chr15-42410926-G-C
• chr15-42410926-G-T

Variant summary

Our verdict is Pathogenic. The variant received 9 ACMG points: 9P and 0B. PM3 PP3 PP4 PM2_Supporting PP1_Strong

This summary comes from the ClinGen Evidence Repository: The NM_000070.3: c.2306G>A variant in CAPN3 is a missense variant predicted to cause the substitution of arginine by glutamine at amino acid position 769, p.(Arg769Gln). The variant has been detected in a homozygous state in more than 30 individuals with LGMD (1.0 pt, PMID:14645990, 12461690, 7720071, 23553538, LOVD CAPN3_000013; PM3). It was also observed to segregate with autosomal recessive LGMD in eight affected family members from two families and was found in a homozygous state in all affected patients in 10 families from the Plain community in northern Indiana (PMID:12461690, 7720071; PP1_Strong). At least one patient homozygous for this variant showed progressive limb girdle muscle weakness and absent expression of calpain-3 protein in skeletal muscle, which is highly specific for CAPN3-related LGMD (PMID:14645990; PP4 (capped with PP1_Strong)). The filtering allele frequency of this variant is 0.000089887 in gnomAD v4.1.0 exomes (the upper threshold of the 95% CI of 3/86258 South Asian chromosomes), which is less than the ClinGen LGMD VCEP threshold (≤0.0001) (PM2_Supporting). The computational predictor REVEL gives a score of 0.947, which is above the threshold of 0.70 (PP3). SpliceAI predicts the possible loss of an alternate splice donor site due to this variant, with a score of 0.49. However, a minigene assay for this variant demonstrated a largely preserved expression of transcripts with normal splicing (PMID:32668095). In summary, this variant is classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 04/22/2025). While the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP, result in 9 Bayesian points (PM3, PP1_Strong, PP4, PM2_Supporting, PP3), a classification of Pathogenic was awarded given the strength of the available evidence and the impact of scoring caps on homozygous case data and locus-specific segregation and phenotype evidence. LINK:https://erepo.genome.network/evrepo/ui/classification/CA127306/MONDO:0015152/187

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000023 (0 hom.)
• Consequence: CAPN3 NM_000070.3 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:14 O:1
• Conservation: PhyloP100: 10.0
• Publications: 19 publications found

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]

CAPN3 Gene-Disease associations (from GenCC):

• muscular dystrophy, limb-girdle, autosomal dominant

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• autosomal recessive limb-girdle muscular dystrophy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• autosomal recessive limb-girdle muscular dystrophy type 2A

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Myriad Women’s Health, Orphanet, Labcorp Genetics (formerly Invitae)
• limb-girdle muscular dystrophy

  Inheritance: SD Classification: DEFINITIVE Submitted by: ClinGen
• muscular dystrophy, limb-girdle, autosomal dominant 4

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ENSG00000258461 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 9 ACMG points.

• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM3: For more information check the summary or visit ClinGen Evidence Repository.
• PP1: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000070.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CAPN3	NM_000070.3	MANE Select	c.2306G>A	p.Arg769Gln	missense	Exon 22 of 24	NP_000061.1	P20807-1
	CAPN3	NM_024344.2		c.2288G>A	p.Arg763Gln	missense	Exon 21 of 23	NP_077320.1	P20807-3
	CAPN3	NM_173087.2		c.2030G>A	p.Arg677Gln	missense	Exon 19 of 21	NP_775110.1	P20807-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CAPN3	ENST00000397163.8	TSL:1 MANE Select	c.2306G>A	p.Arg769Gln	missense	Exon 22 of 24	ENSP00000380349.3	P20807-1
	CAPN3	ENST00000357568.8	TSL:1	c.2288G>A	p.Arg763Gln	missense	Exon 21 of 23	ENSP00000350181.3	P20807-3
	CAPN3	ENST00000349748.8	TSL:1	c.2030G>A	p.Arg677Gln	missense	Exon 19 of 21	ENSP00000183936.4	P20807-2

Frequencies

GnomAD3 genomes AF: 0.000125 AC: 19 AN: 152202 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.0154

Gnomad AMR AF: 0.0000655

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000318 AC: 8 AN: 251404 AF XY: 0.0000368

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS 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: 0.0000233 AC: 34 AN: 1461856 Hom.: 0 Cov.: 32 AF XY: 0.0000289 AC XY: 21 AN XY: 727236

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000261 AC: 29 AN: 1111976

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome AF: 0.000125 AC: 19 AN: 152202 Hom.: 0 Cov.: 31 AF XY: 0.000108 AC XY: 8 AN XY: 74354

African (AFR) AF: 0.0000724 AC: 3 AN: 41438

American (AMR) AF: 0.0000655 AC: 1 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68036

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000573 Hom.: 0

Bravo AF: 0.000178

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000494 AC: 6

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
5	-	-	Autosomal recessive limb-girdle muscular dystrophy type 2A (6)
5	-	-	not provided (5)
2	-	-	Autosomal recessive limb-girdle muscular dystrophy (2)
1	-	-	Autosomal recessive limb-girdle muscular dystrophy type 2A;C4748295:Muscular dystrophy, limb-girdle, autosomal dominant 4 (1)
1	-	-	Muscular dystrophy, limb-girdle, autosomal dominant 4 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	34
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.090	T
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.99
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.45	D
MetaRNN	Benign	0.42	T
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.4	M
PhyloP100		10
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-3.5	D
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.98
MVP		0.99
MPC		0.68
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.93
gMVP		0.91
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		3.0
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs80338802; hg19: chr15-42703124; COSMIC: COSV55518596; COSMIC: COSV55518596;