rs863224957

chr15-42401751-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM5 PP3_Strong PP5_Very_Strong

The NM_000070.3(CAPN3):c.1465C>T(p.Arg489Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000359 in 1,613,928 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R489Q) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000039 (0 hom.)
• Consequence: CAPN3 NM_000070.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 1.41

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]

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_000070.3
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr15-42401752-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 289644.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.978
• PP5: Variant 15-42401751-C-T is Pathogenic according to our data. Variant chr15-42401751-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 217150.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-42401751-C-T is described in Lovd as [Pathogenic]. Variant chr15-42401751-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CAPN3	NM_000070.3	c.1465C>T	p.Arg489Trp	missense_variant	11/24	ENST00000397163.8
CAPN3	NM_024344.2	c.1465C>T	p.Arg489Trp	missense_variant	11/23
CAPN3	NM_173087.2	c.1321C>T	p.Arg441Trp	missense_variant	10/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CAPN3	ENST00000397163.8	c.1465C>T	p.Arg489Trp	missense_variant	11/24	1	NM_000070.3	P2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152092 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000159 AC: 4 AN: 251280 Hom.: 0 AF XY: 0.0000295 AC XY: 4 AN XY: 135808

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000390 AC: 57 AN: 1461836 Hom.: 0 Cov.: 33 AF XY: 0.0000371 AC XY: 27 AN XY: 727220

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000450

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152092 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74284

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000508 Hom.: 0

Bravo AF: 0.00000756

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal recessive limb-girdle muscular dystrophy type 2A Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 24, 2024	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 489 of the CAPN3 protein (p.Arg489Trp). This variant is present in population databases (no rsID available, gnomAD 0.003%). This missense change has been observed in individual(s) with autosomal recessive limb-girdle muscular dystrophy (PMID: 9762961, 16141003, 18055493, 25135358, 27708273; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 217150). 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%. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Counsyl	Feb 09, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Intergen, Intergen Genetics and Rare Diseases Diagnosis Center	Aug 31, 2023	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 19, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 23, 2016	- -

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

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Oct 30, 2023

- -

Autosomal recessive limb-girdle muscular dystrophy type 2A;C4748295:Muscular dystrophy, limb-girdle, autosomal dominant 4 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Nov 19, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.31
Cadd	Pathogenic	31
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.66	D;.;.;D
Eigen	Benign	0.085
Eigen_PC	Benign	-0.045
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Uncertain	0.91	D;D;D;D
M_CAP	Pathogenic	0.47	D
MetaRNN	Pathogenic	0.98	D;D;D;D
MetaSVM	Uncertain	0.55	D
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Pathogenic	0.87	D
REVEL	Pathogenic	0.75
Sift4G	Benign	0.077	T;T;T;T
Polyphen		1.0	.;D;D;D
Vest4		0.98
MutPred		0.89		.;Loss of disorder (P = 0.02);.;Loss of disorder (P = 0.02);
MVP		0.92
MPC		0.64
ClinPred		0.98	D
GERP RS		-0.18
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.73
gMVP		0.82

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs863224957; hg19: chr15-42693949; COSMIC: COSV100520606; COSMIC: COSV100520606;