15-42403763-G-T

Variant names:

• chr15-42403763-G-T
• rs370809015
• NM_000070.3:c.1768G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000070.3(CAPN3):​c.1768G>T​(p.Val590Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V590M) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CAPN3 NM_000070.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 6.58
• Publications: 8 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.22053069).

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.1768G>T	p.Val590Leu	missense	Exon 14 of 24	NP_000061.1
	CAPN3	NM_024344.2		c.1768G>T	p.Val590Leu	missense	Exon 14 of 23	NP_077320.1
	CAPN3	NM_173087.2		c.1624G>T	p.Val542Leu	missense	Exon 13 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.1768G>T	p.Val590Leu	missense	Exon 14 of 24	ENSP00000380349.3
	CAPN3	ENST00000357568.8	TSL:1	c.1768G>T	p.Val590Leu	missense	Exon 14 of 23	ENSP00000350181.3
	CAPN3	ENST00000349748.8	TSL:1	c.1624G>T	p.Val542Leu	missense	Exon 13 of 21	ENSP00000183936.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

Autosomal recessive limb-girdle muscular dystrophy type 2A Uncertain:2

Sep 16, 2020

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

Dec 10, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 590 of the CAPN3 protein (p.Val590Leu). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with CAPN3-related conditions. ClinVar contains an entry for this variant (Variation ID: 536511). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on CAPN3 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Uncertain	0.062	T
BayesDel_noAF	Benign	-0.15
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.17	T
Eigen	Benign	-0.19
Eigen_PC	Benign	0.0088
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.078	D
MetaRNN	Benign	0.22	T
MetaSVM	Benign	-0.38	T
MutationAssessor	Benign	0.90	L
PhyloP100		6.6
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.18
Sift	Benign	0.065	T
Sift4G	Benign	0.61	T
Polyphen		0.0080	B
Vest4		0.27
MutPred		0.30		Loss of MoRF binding (P = 0.1056)
MVP		0.86
MPC		0.14
ClinPred		0.76	D
GERP RS		4.8
Varity_R		0.13
gMVP		0.35

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs370809015; hg19: chr15-42695961;