15-42409972-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PP3_StrongPP5

The ENST00000673743.1(CAPN3):​c.-6C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000496 in 1,612,032 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 31)
Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

CAPN3
ENST00000673743.1 5_prime_UTR_premature_start_codon_gain

Scores

14
3
2

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:7U:1

Conservation

PhyloP100: 3.17

Publications

4 publications found
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 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

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

PP3
MetaRNN computational evidence supports a deleterious effect, 0.984
PP5
Variant 15-42409972-C-T is Pathogenic according to our data. Variant chr15-42409972-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 285572.We mark this variant Pathogenic, oryginal submission is: [Conflicting_classifications_of_pathogenicity].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CAPN3NM_000070.3 linkc.2092C>T p.Arg698Cys missense_variant Exon 19 of 24 ENST00000397163.8 NP_000061.1 P20807-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CAPN3ENST00000673743.1 linkc.-6C>T 5_prime_UTR_premature_start_codon_gain_variant Exon 6 of 11 ENSP00000500989.1 A0A669KAX6
CAPN3ENST00000397163.8 linkc.2092C>T p.Arg698Cys missense_variant Exon 19 of 24 1 NM_000070.3 ENSP00000380349.3 P20807-1
CAPN3ENST00000673886.1 linkc.97C>T p.Arg33Cys missense_variant Exon 6 of 11 ENSP00000501155.1 P20807-5
CAPN3ENST00000673928.1 linkc.97C>T p.Arg33Cys missense_variant Exon 6 of 11 ENSP00000501099.1 P20807-5
CAPN3ENST00000674146.1 linkc.97C>T p.Arg33Cys missense_variant Exon 7 of 12 ENSP00000501175.1 P20807-5
CAPN3ENST00000674149.1 linkc.97C>T p.Arg33Cys missense_variant Exon 6 of 11 ENSP00000501112.1 P20807-5
ENSG00000258461ENST00000495723.1 linkn.*2528C>T non_coding_transcript_exon_variant Exon 21 of 26 2 ENSP00000492063.1 A0A1W2PQD3
CAPN3ENST00000673743.1 linkc.-6C>T 5_prime_UTR_variant Exon 6 of 11 ENSP00000500989.1 A0A669KAX6
ENSG00000258461ENST00000495723.1 linkn.*2528C>T 3_prime_UTR_variant Exon 21 of 26 2 ENSP00000492063.1 A0A1W2PQD3

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152110
Hom.:
0
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.0000241
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
GnomAD2 exomes
AF:
0.0000159
AC:
4
AN:
251334
AF XY:
0.0000221
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000289
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000264
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000411
AC:
6
AN:
1459922
Hom.:
0
Cov.:
34
AF XY:
0.00000688
AC XY:
5
AN XY:
726256
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33412
American (AMR)
AF:
0.0000224
AC:
1
AN:
44716
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26134
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39700
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86180
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53420
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
4294
European-Non Finnish (NFE)
AF:
0.00000450
AC:
5
AN:
1111840
Other (OTH)
AF:
0.00
AC:
0
AN:
60226
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.450
Heterozygous variant carriers
0
1
2
3
4
5
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152110
Hom.:
0
Cov.:
31
AF XY:
0.0000135
AC XY:
1
AN XY:
74304
show subpopulations
African (AFR)
AF:
0.0000241
AC:
1
AN:
41414
American (AMR)
AF:
0.00
AC:
0
AN:
15278
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3472
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5168
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4832
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10604
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.0000147
AC:
1
AN:
68022
Other (OTH)
AF:
0.00
AC:
0
AN:
2092
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.500
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.00
Hom.:
0
Bravo
AF:
0.0000113
ExAC
AF:
0.0000165
AC:
2

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:7Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Autosomal recessive limb-girdle muscular dystrophy type 2A Pathogenic:5
Mar 07, 2023
Illumina Laboratory Services, Illumina
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The CAPN3 c.2092C>T (p.Arg698Cys) missense variant results in the substitution of arginine at amino acid position 698 with cysteine. This variant has been reported in the literature in at least six individuals with autosomal recessive limb-girdle muscular dystrophy (LGMD), including in a homozygous state in one individual and in a compound heterozygous state in five individuals (PMID: 16650086; PMID: 17236769; PMID: 21204801; PMID: 28403181; PMID: 33250842; PMID: 35169782). Additionally, two different amino acid substitutions at the same codon (Arg698His, Arg698Pro) have been reported in individuals with LGMD (PMID: 25135358; PMID: 10330340). This variant is reported in the Genome Aggregation Database at a frequency of 0.000029 in the Latino/Admixed American population (version 2.1.1). The c.2092C>T variant is located within EF-hand 2 domain, which has a low rate of benign variation (UniProt:P20807; PMID: 35169782). Based on the available evidence, the c.2092C>T (p.Arg698Cys) variant is classified as pathogenic for limb-girdle muscular dystrophy. -

May 10, 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. -

Oct 14, 2022
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics
Significance:Likely pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

A homozygous variation in exon 19 of the CAPN3 gene that results in the amino acid substitution cysteine for arginine at codon 698 was detected. The observed variant reported in the 1000 genomes and gnomAD databases. The in silico predictions of the variant are probably damaging by PolyPhen-2 (HumDiv) and damaging by SIFT and MutationTaster2. The reference codon is conserved across species. -

Jan 29, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 698 of the CAPN3 protein (p.Arg698Cys). This variant is present in population databases (rs764370512, gnomAD 0.003%). This missense change has been observed in individual(s) with autosomal recessive limb-girdle muscular dystrophy (PMID: 15689361, 16650086, 21204801, 28403181). ClinVar contains an entry for this variant (Variation ID: 285572). 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.Arg698 amino acid residue in CAPN3. Other variant(s) that disrupt this residue have been observed in individuals with CAPN3-related conditions (PMID: 16411092, 25135358), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -

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 homozygous p.Arg698Cys variant in CAPN3 was identified by our study in two unrelated individuals with limb-girdle muscular dystrophy (LGMD). The p.Arg698Cys variant has also been reported in at least 8 individuals with limb-girdle muscular dystrophy (PMID: 15689361, 17236769, 16650086, 21204801, 28403181, 33250842, 35169782, 35821219), and has been identified in 0.002% (1/59994) of Admixed American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs764370512). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (Variation ID: 285572) and has been interpreted as likely pathogenic/pathogenic by multiple labs. Of the affected individuals, five were compound heterozygotes that carried reported pathogenic variant with unknown phase and two were homozygotes, which increases the likelihood that the p.Arg698Cys variant is pathogenic (Variation ID: 17621, 128570, 468648, 557732, 2680368; PMID: 17236769, 21204801, 28403181, 33250842, 35169782, 35821219). 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 vitro functional studies provide some evidence that the p.Arg698Cys variant may slightly impact protein function (PMID: 17236769). However, these types of assays may not accurately represent biological function. 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, PS3_supporting (Richards 2015). -

not provided Pathogenic:1Uncertain:1
Jan 22, 2016
Eurofins Ntd Llc (ga)
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Jan 03, 2020
Revvity Omics, Revvity
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Muscular dystrophy, limb-girdle, autosomal dominant 4 Pathogenic:1
Dec 02, 2023
Baylor Genetics
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.70
BayesDel_addAF
Pathogenic
0.34
D
BayesDel_noAF
Pathogenic
0.33
CADD
Pathogenic
30
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.26
T;.;.;D;.;.;.;.;.;.;.;.
Eigen
Pathogenic
0.74
Eigen_PC
Uncertain
0.59
FATHMM_MKL
Uncertain
0.88
D
LIST_S2
Pathogenic
0.99
D;D;D;D;D;D;.;D;.;D;.;D
M_CAP
Pathogenic
0.41
D
MetaRNN
Pathogenic
0.98
D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
0.87
D
MutationAssessor
Pathogenic
3.7
.;.;.;H;.;.;.;.;.;.;.;.
PhyloP100
3.2
PrimateAI
Uncertain
0.72
T
PROVEAN
Pathogenic
-6.5
.;D;D;D;D;D;D;.;D;D;D;D
REVEL
Pathogenic
0.94
Sift
Pathogenic
0.0
.;D;D;D;D;D;D;.;D;D;D;D
Sift4G
Pathogenic
0.0
D;D;D;D;D;D;D;D;D;D;D;D
Polyphen
1.0
.;D;D;D;.;.;.;.;.;.;.;.
Vest4
0.99
MutPred
0.93
.;.;.;Gain of catalytic residue at A702 (P = 0.1683);.;.;.;.;.;.;.;.;
MVP
0.95
MPC
0.74
ClinPred
0.96
D
GERP RS
3.9
Varity_R
0.79
gMVP
0.78
Mutation Taster
=0/100
disease causing (ClinVar)

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Other links and lift over

dbSNP: rs764370512; hg19: chr15-42702170; API