rs777323132

Positions:

chr15-42399616-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM5PP3_StrongPP5_Very_Strong

The NM_000070.3(CAPN3):c.1318C>T(p.Arg440Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000174 in 1,611,092 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. R440Q) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000019 ( 0 hom. )

Consequence

CAPN3
NM_000070.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: 1.66

Variant links:

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 links:

ENSG00000258461 (HGNC:):

ENSG00000258461 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PM1

In a region_of_interest Domain III (size 168) in uniprot entity CAN3_HUMAN there are 132 pathogenic changes around while only 0 benign (100%) in NM_000070.3

PM5

Other missense variant is known to change same aminoacid residue: Variant chr15-42399617-G-A is described in Lovd as [Pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.956

PP5

Variant 15-42399616-C-T is Pathogenic according to our data. Variant chr15-42399616-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 283991.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-42399616-C-T is described in Lovd as [Pathogenic]. Variant chr15-42399616-C-T is described in Lovd as [Likely_pathogenic]. Variant chr15-42399616-C-T is described in Lovd as [Likely_pathogenic]. Variant chr15-42399616-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CAPN3	NM_000070.3 linkuse as main transcript	c.1318C>T	p.Arg440Trp	missense_variant	10/24	ENST00000397163.8	NP_000061.1	P20807-1
CAPN3	NM_024344.2 linkuse as main transcript	c.1318C>T	p.Arg440Trp	missense_variant	10/23		NP_077320.1	P20807-3
CAPN3	NM_173087.2 linkuse as main transcript	c.1174C>T	p.Arg392Trp	missense_variant	9/21		NP_775110.1	P20807-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
CAPN3	ENST00000397163.8 linkuse as main transcript	c.1318C>T	p.Arg440Trp	missense_variant	10/24	1	NM_000070.3	ENSP00000380349.3	P20807-1
ENSG00000258461	ENST00000495723.1 linkuse as main transcript	n.*1114C>T		non_coding_transcript_exon_variant	14/26	2		ENSP00000492063.1	A0A1W2PQD3
ENSG00000258461	ENST00000495723.1 linkuse as main transcript	n.*1114C>T		3_prime_UTR_variant	14/26	2		ENSP00000492063.1	A0A1W2PQD3

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152200

Hom.:

Cov.:

show subpopulations

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:

0.0000242

AC:

AN:

247520

Hom.:

AF XY:

0.0000299

AC XY:

AN XY:

133934

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000330

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000448

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000185

AC:

AN:

1458892

Hom.:

Cov.:

AF XY:

0.0000165

AC XY:

AN XY:

725306

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000697

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000171

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152200

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74352

show subpopulations

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:

0.0000254

Hom.:

Bravo

AF:

0.0000302

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Autosomal recessive limb-girdle muscular dystrophy type 2A

Pathogenic:4

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Aug 18, 2020	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Nov 09, 2017	- -
Likely pathogenic, criteria provided, single submitter	research	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	Apr 16, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 24, 2023	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 440 of the CAPN3 protein (p.Arg440Trp). This variant is present in population databases (rs777323132, gnomAD 0.005%). This missense change has been observed in individuals with autosomal recessive limb-girdle muscular dystrophy (PMID: 9150160, 11525884, 22926650, 26060040). ClinVar contains an entry for this variant (Variation ID: 283991). 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 expected to disrupt CAPN3 protein function with a positive predictive value of 80%. This variant disrupts the p.Arg440 amino acid residue in CAPN3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15221789, 18055493, 19048948, 20694146, 21984748, 25326637). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

not provided

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 03, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 12, 2018	- -

Muscular dystrophy, limb-girdle, autosomal dominant 4

Pathogenic:1

Pathogenic, flagged submission

clinical testing

Baylor Genetics

Oct 22, 2023

- -

Abnormality of the musculature

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Kariminejad - Najmabadi Pathology & Genetics Center

Jul 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.85

BayesDel_addAF

Pathogenic

0.34

BayesDel_noAF

Pathogenic

0.38

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.75

D;.;.;D

Eigen

Uncertain

0.36

Eigen_PC

Uncertain

0.23

FATHMM_MKL

Uncertain

0.86

LIST_S2

Uncertain

0.96

D;D;D;D

M_CAP

Uncertain

0.28

MetaRNN

Pathogenic

0.96

D;D;D;D

MetaSVM

Pathogenic

0.90

MutationAssessor

Pathogenic

3.9

.;H;.;H

PrimateAI

Pathogenic

0.86

PROVEAN

Pathogenic

-7.1

.;D;D;D

REVEL

Pathogenic

0.90

Sift

Pathogenic

0.0

.;D;D;D

Sift4G

Pathogenic

0.0010

D;D;D;D

Polyphen

1.0

.;D;D;D

Vest4

0.91

MVP

0.94

MPC

0.64

ClinPred

1.0

GERP RS

1.6

Varity_R

0.90

gMVP

0.86

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over