rs898013388

Positions:

• chr15-42359998-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_000070.3(CAPN3):​c.193C>G​(p.His65Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,878 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: CAPN3 NM_000070.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 2.17

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CAPN3	NM_000070.3	c.193C>G	p.His65Asp	missense_variant	1/24	ENST00000397163.8	NP_000061.1
CAPN3	NM_024344.2	c.193C>G	p.His65Asp	missense_variant	1/23		NP_077320.1
CAPN3	NM_173087.2	c.193C>G	p.His65Asp	missense_variant	1/21		NP_775110.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CAPN3	ENST00000397163.8	c.193C>G	p.His65Asp	missense_variant	1/24	1	NM_000070.3	ENSP00000380349.3
ENSG00000258461	ENST00000495723.1	n.*105+5545C>G		intron_variant		2		ENSP00000492063.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461878 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 727236

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00000270

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

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

Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Oct 07, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jun 27, 2022	This sequence change replaces histidine, which is basic and polar, with aspartic acid, which is acidic and polar, at codon 65 of the CAPN3 protein (p.His65Asp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal recessive limb-girdle muscular dystrophy (LGMD) (PMID: 18055493). ClinVar contains an entry for this variant (Variation ID: 536515). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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 v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.67
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.26
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.028	T;.;.;T
Eigen	Benign	-0.11
Eigen_PC	Benign	0.084
FATHMM_MKL	Benign	0.58	D
LIST_S2	Benign	0.81	T;T;D;T
M_CAP	Benign	0.045	D
MetaRNN	Uncertain	0.68	D;D;D;D
MetaSVM	Uncertain	0.25	D
MutationAssessor	Benign	0.69	.;N;N;N
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-2.0	N;N;N;N
REVEL	Uncertain	0.57
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D
Polyphen		0.070, 0.030, 0.042	.;B;B;B
Vest4		0.45
MutPred		0.85		Gain of ubiquitination at K67 (P = 0.0495);Gain of ubiquitination at K67 (P = 0.0495);Gain of ubiquitination at K67 (P = 0.0495);Gain of ubiquitination at K67 (P = 0.0495);
MVP		0.94
MPC		0.22
ClinPred		0.49	T
GERP RS		6.0
Varity_R		0.58
gMVP		0.89

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

Publications

LitVar

Other links and lift over

dbSNP: rs898013388; hg19: chr15-42652196;