rs774685118

Variant names:

• chr15-42386185-C-T
• rs774685118
• NM_000070.3:c.398C>T

Variant summary

Our verdict is Uncertain significance. The variant received 6 ACMG points: 6P and 0B. PP3 PP4 PM3_Strong

This summary comes from the ClinGen Evidence Repository: The NM_000070.3: c.398C>T variant in CAPN3 is a missense variant predicted to cause substitution of alanine by valine at position 133, p.(Ala133Val). This variant has been reported in two unrelated individuals with a clinical diagnosis of LGMD, where it was confirmed in trans with a likely pathogenic or pathogenic variant (c.598_612del p.(Phe200_Leu204del), 1.0 pt x2, PMID:16141003, LOVD individuals #00214184, #00214185; PM3_Strong, PP4). However, it has also been observed in a homozygous state or in trans with a second presumed diagnostic CAPN3 variant (c.133G>A p.(Ala45Thr), c.1303G>A (p.Glu435Lys)) in three individuals without a clear LGMD phenotype (ClinVar SCV001985435.3, SCV003509679.1 internal data communication). The filtering allele frequency of this variant is 0.0001855 (the upper threshold of the 95% CI of 16/86246 exome chromosomes) in the South Asian population in gnomAD v4.1.0, which is greater than the ClinGen LGMD VCEP threshold (≤0.0001) (PM2_Supporting not met). Of note, the South Asian population also includes one homozygous individual of unknown age. The computational predictor REVEL gives a score of 0.959, which is above the LGMD VCEP threshold of ≥0.70, evidence that correlates with impact to CAPN3 function (PP3). In summary, while 6 Bayesian points were awarded to this variant based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (PM3_Strong, PP3, PP4), given the conflicting evidence, the VCEP has opted to classify it as a variant of uncertain significance for autosomal recessive limb girdle muscular dystrophy (LGMD VCEP specifications version 1.0.0; 03/25/2025). LINK:https://erepo.genome.network/evrepo/ui/classification/CA7511008/MONDO:0015152/187

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000021 (1 hom.)
• Consequence: CAPN3 NM_000070.3 missense
• Clinical Significance: Uncertain significance reviewed by expert panel U:9
• Conservation: PhyloP100: 7.91
• Publications: 3 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):

• 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: Orphanet, Myriad Women’s Health, Labcorp Genetics (formerly Invitae)
• muscular dystrophy, limb-girdle, autosomal dominant 4

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• muscular dystrophy, limb-girdle, autosomal dominant

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ENSG00000258461 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 6 ACMG points.

• PM3: 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CAPN3	NM_000070.3	MANE Select	c.398C>T	p.Ala133Val	missense	Exon 3 of 24	NP_000061.1
	CAPN3	NM_024344.2		c.398C>T	p.Ala133Val	missense	Exon 3 of 23	NP_077320.1
	CAPN3	NM_173087.2		c.398C>T	p.Ala133Val	missense	Exon 3 of 21	NP_775110.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CAPN3	ENST00000397163.8	TSL:1 MANE Select	c.398C>T	p.Ala133Val	missense	Exon 3 of 24	ENSP00000380349.3
	CAPN3	ENST00000357568.8	TSL:1	c.398C>T	p.Ala133Val	missense	Exon 3 of 23	ENSP00000350181.3
	CAPN3	ENST00000349748.8	TSL:1	c.398C>T	p.Ala133Val	missense	Exon 3 of 21	ENSP00000183936.4

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152190 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: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000597 AC: 15 AN: 251410 AF XY: 0.0000662

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.0000289

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: 0.0000212 AC: 31 AN: 1461364 Hom.: 1 Cov.: 31 AF XY: 0.0000220 AC XY: 16 AN XY: 727050

African (AFR) AF: 0.0000598 AC: 2 AN: 33466

American (AMR) AF: 0.0000224 AC: 1 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000186 AC: 16 AN: 86246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53388

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.00000630 AC: 7 AN: 1111560

Other (OTH) AF: 0.0000662 AC: 4 AN: 60384

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152190 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74348

African (AFR) AF: 0.0000241 AC: 1 AN: 41432

American (AMR) AF: 0.00 AC: 0 AN: 15284

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68032

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

Alfa AF: 0.0000687 Hom.: 0

Bravo AF: 0.0000227

ExAC AF: 0.0000412 AC: 5

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	4	-	not provided (4)
-	3	-	Autosomal recessive limb-girdle muscular dystrophy type 2A (3)
-	1	-	Autosomal recessive limb-girdle muscular dystrophy (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	31
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.52	D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.93	D
M_CAP	Pathogenic	0.64	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.8	H
PhyloP100		7.9
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-3.8	D
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.76
MutPred		0.92		Gain of loop (P = 0.2045)
MVP		0.98
MPC		0.63
ClinPred		0.98	D
GERP RS		6.1
Varity_R		0.91
gMVP		0.86
Mutation Taster		=0/100	disease causing

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

Other links and lift over

dbSNP: rs774685118; hg19: chr15-42678383;