rs1555420765

Positions:

• chr15-42389999-T-C

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM2 PM5 PP3 PP5_Very_Strong

The NM_000070.3(CAPN3):​c.848T>C​(p.Met283Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,848 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M283V) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CAPN3 NM_000070.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 4.70

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 13 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr15-42389998-A-G is described in Lovd as [Likely_pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.817
• PP5: Variant 15-42389999-T-C is Pathogenic according to our data. Variant chr15-42389999-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 555646.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-42389999-T-C is described in Lovd as [Pathogenic]. Variant chr15-42389999-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CAPN3	NM_000070.3	c.848T>C	p.Met283Thr	missense_variant	6/24	ENST00000397163.8	NP_000061.1
CAPN3	NM_024344.2	c.848T>C	p.Met283Thr	missense_variant	6/23		NP_077320.1
CAPN3	NM_173087.2	c.801+903T>C		intron_variant			NP_775110.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CAPN3	ENST00000397163.8	c.848T>C	p.Met283Thr	missense_variant	6/24	1	NM_000070.3	ENSP00000380349.3
ENSG00000258461	ENST00000495723.1	n.*644T>C		non_coding_transcript_exon_variant	10/26	2		ENSP00000492063.1
ENSG00000258461	ENST00000495723.1	n.*644T>C		3_prime_UTR_variant	10/26	2		ENSP00000492063.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461848 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727226

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Dec 19, 2017	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jun 09, 2023	In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt CAPN3 protein function. ClinVar contains an entry for this variant (Variation ID: 555646). This missense change has been observed in individual(s) with clinical features of autosomal recessive limb-girdle muscular dystrophy (PMID: 15221789, 25046369, 26404900). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 283 of the CAPN3 protein (p.Met283Thr). -

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

Likely pathogenic, flagged submission

clinical testing

Baylor Genetics

Jul 29, 2023

- -

Autosomal recessive limb-girdle muscular dystrophy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Sep 03, 2021

Variant summary: CAPN3 c.848T>C (p.Met283Thr) results in a non-conservative amino acid change located in the Peptidase C2, calpain, catalytic domain (IPR001330) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 251486 control chromosomes. c.848T>C has been reported in the literature as a compound heterozygous/homozygous genotype in multiple individuals affected with Limb-Girdle Muscular Dystrophy, Autosomal Recessive (example, Fanin_2004, Bartoli_2014, Magri_2015, Barp_2020, Dionnet_2020). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in complete absence of the Calpain-3 protein staining upon western blot analysis (Fanin_2004). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.23
CADD	Uncertain	23
DANN	Benign	0.95
DEOGEN2	Benign	0.11	.;T
Eigen	Benign	0.030
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.79	T;T
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.82	D;D
MetaSVM	Uncertain	-0.044	T
MutationAssessor	Benign	0.34	N;N
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-0.78	N;N
REVEL	Uncertain	0.54
Sift	Benign	0.080	T;T
Sift4G	Benign	0.27	T;T
Polyphen		0.17	B;B
Vest4		0.52
MutPred		0.89		Gain of phosphorylation at M283 (P = 0.0652);Gain of phosphorylation at M283 (P = 0.0652);
MVP		0.89
MPC		0.20
ClinPred		0.36	T
GERP RS		5.9
Varity_R		0.20
gMVP		0.73

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1555420765; hg19: chr15-42682197;