rs1555420468

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong

The NM_000070.3(CAPN3):c.509A>G(p.Tyr170Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000186 in 1,614,204 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 (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

CAPN3
NM_000070.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 6.09

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 strand (size 9) in uniprot entity CAN3_HUMAN there are 7 pathogenic changes around while only 0 benign (100%) in NM_000070.3

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.978

PP5

Variant 15-42387763-A-G is Pathogenic according to our data. Variant chr15-42387763-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 557074.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-42387763-A-G is described in Lovd as [Likely_pathogenic]. Variant chr15-42387763-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CAPN3	NM_000070.3 link	c.509A>G	p.Tyr170Cys	missense_variant	Exon 4 of 24	ENST00000397163.8	NP_000061.1	P20807-1
CAPN3	NM_024344.2 link	c.509A>G	p.Tyr170Cys	missense_variant	Exon 4 of 23		NP_077320.1	P20807-3
CAPN3	NM_173087.2 link	c.509A>G	p.Tyr170Cys	missense_variant	Exon 4 of 21		NP_775110.1	P20807-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CAPN3	ENST00000397163.8 link	c.509A>G	p.Tyr170Cys	missense_variant	Exon 4 of 24	1	NM_000070.3	ENSP00000380349.3	P20807-1
ENSG00000258461	ENST00000495723.1 link	n.*305A>G		non_coding_transcript_exon_variant	Exon 8 of 26	2		ENSP00000492063.1	A0A1W2PQD3
ENSG00000258461	ENST00000495723.1 link	n.*305A>G		3_prime_UTR_variant	Exon 8 of 26	2		ENSP00000492063.1	A0A1W2PQD3

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152206

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:

0.000192

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251474

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135908

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:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461880

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727242

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

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

AF:

0.00000656

AC:

AN:

152324

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74494

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Autosomal recessive limb-girdle muscular dystrophy type 2A

Pathogenic:3

Apr 11, 2024

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

The p.Tyr170Cys variant in CAPN3 was identified by our study in 2 siblings with autosomal recessive limb-girdle muscular dystrophy, in the compound heterozygous state along with another pathogenic variant. The phase of these variants are unknown at this time. The p.Tyr170Cys variant has also been reported in 4 individuals with limb-girdle muscular dystrophy (PMID: 18055493, 23821418, 25135358), and has been identified in 0.002% (1/44892) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP: rs1555420468). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (Variation ID: 557074) and has been interpreted as likely pathogenic by Counsyl and pathogenic by Invitae. Of the five affected individuals, four were compound heterozygotes that carried a reported pathogenic variant with unknown phase, which increases the likelihood that the p.Tyr170Cys variant is pathogenic (Variation ID: 17621, 283259; (PMID: 18055493, 23821418, 25135358). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for autosomal recessive limb-girdle muscular dystrophy. ACMG/AMP Criteria applied: PM3_strong, PP3_moderate, PM2_supporting (Richards 2015). -

Mar 07, 2018

Counsyl

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 09, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 170 of the CAPN3 protein (p.Tyr170Cys). 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 (PMID: 18055493, 23821418, 25135358, 31127727; external communication). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 557074). 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.59

BayesDel_addAF

Pathogenic

0.42

BayesDel_noAF

Pathogenic

0.37

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.34

T;.;.;D

Eigen

Pathogenic

0.83

Eigen_PC

Pathogenic

0.81

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.90

D;D;D;D

M_CAP

Pathogenic

0.33

MetaRNN

Pathogenic

0.98

D;D;D;D

MetaSVM

Pathogenic

0.81

MutationAssessor

Uncertain

2.4

.;M;M;M

PrimateAI

Uncertain

0.74

PROVEAN

Pathogenic

-7.0

D;D;D;D

REVEL

Pathogenic

0.93

Sift

Uncertain

0.0020

D;D;D;D

Sift4G

Uncertain

0.0020

D;D;D;D

Polyphen

1.0

.;D;D;D

Vest4

0.92

MutPred

0.90

Gain of sheet (P = 0.1208);Gain of sheet (P = 0.1208);Gain of sheet (P = 0.1208);Gain of sheet (P = 0.1208);

MVP

0.97

MPC

0.71

ClinPred

0.99

GERP RS

6.0

Varity_R

0.95

gMVP

0.81

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