rs1555420765

Variant names:

• chr15-42389999-T-C
• rs1555420765
• NM_000070.3:c.848T>C

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM2 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 Uncertain significance.

• 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:5
• Conservation: PhyloP100: 4.70
• Publications: 0 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: Pathogenic. The variant received 11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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 Pathogenic/Likely_pathogenic. ClinVar VariationId is 555646.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.848T>C	p.Met283Thr	missense	Exon 6 of 24	NP_000061.1
	CAPN3	NM_024344.2		c.848T>C	p.Met283Thr	missense	Exon 6 of 23	NP_077320.1
	CAPN3	NM_173087.2		c.801+903T>C		intron	N/A	NP_775110.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CAPN3	ENST00000397163.8	TSL:1 MANE Select	c.848T>C	p.Met283Thr	missense	Exon 6 of 24	ENSP00000380349.3
	CAPN3	ENST00000357568.8	TSL:1	c.848T>C	p.Met283Thr	missense	Exon 6 of 23	ENSP00000350181.3
	ENSG00000258461	ENST00000495723.1	TSL:2	n.*644T>C		non_coding_transcript_exon	Exon 10 of 26	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

African (AFR) AF: 0.00 AC: 0 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: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 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: 0.00000180 AC: 2 AN: 1111972

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Mar 01, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of autosomal recessive limb-girdle muscular dystrophy (PMID: 15221789, 25046369, 26404900). ClinVar contains an entry for this variant (Variation ID: 555646). 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 with a negative predictive value of 80%. 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.

Dec 19, 2017

Counsyl

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.

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

Jul 29, 2023

Baylor Genetics

Significance: Likely pathogenic

Review Status: flagged submission

Collection Method: clinical testing

Autosomal recessive limb-girdle muscular dystrophy Pathogenic:1

Sep 03, 2021

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

not provided Pathogenic:1

Oct 09, 2023

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.82	D
MetaSVM	Uncertain	-0.044	T
MutationAssessor	Benign	0.34	N
PhyloP100		4.7
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-0.78	N
REVEL	Uncertain	0.54
Sift	Benign	0.080	T
Sift4G	Benign	0.27	T
Polyphen		0.17	B
Vest4		0.52
MutPred		0.89		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
Mutation Taster		=8/92	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		1.0
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

Other links and lift over

dbSNP: rs1555420765; hg19: chr15-42682197;