rs200379491

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 11P and 1B. PM1PP3PP5_Very_StrongBP4

The NM_000070.3(CAPN3):​c.2120A>G​(p.Asp707Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000465 in 1,614,114 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., cov: 31)
Exomes 𝑓: 0.000044 ( 0 hom. )

Consequence

CAPN3
NM_000070.3 missense

Scores

11
4
4

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:15

Conservation

PhyloP100: 7.48
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PM1
In a binding_site (size 0) in uniprot entity CAN3_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_000070.3
PP3
Multiple lines of computational evidence support a deleterious effect 9: AlphaMissense, BayesDel_addAF, BayesDel_noAF, Cadd, Eigen, M_CAP, MutationAssessor, PROVEAN, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
PP5
Variant 15-42410432-A-G is Pathogenic according to our data. Variant chr15-42410432-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 468648.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-42410432-A-G is described in Lovd as [Pathogenic]. Variant chr15-42410432-A-G is described in Lovd as [Pathogenic]. Variant chr15-42410432-A-G is described in Lovd as [Likely_pathogenic]. Variant chr15-42410432-A-G is described in Lovd as [Likely_pathogenic].
BP4
Computational evidence support a benign effect (MetaRNN=0.39079383). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CAPN3NM_000070.3 linkc.2120A>G p.Asp707Gly missense_variant Exon 20 of 24 ENST00000397163.8 NP_000061.1 P20807-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CAPN3ENST00000397163.8 linkc.2120A>G p.Asp707Gly missense_variant Exon 20 of 24 1 NM_000070.3 ENSP00000380349.3 P20807-1
CAPN3ENST00000673886.1 linkc.125A>G p.Asp42Gly missense_variant Exon 7 of 11 ENSP00000501155.1 P20807-5
CAPN3ENST00000673928.1 linkc.125A>G p.Asp42Gly missense_variant Exon 7 of 11 ENSP00000501099.1 P20807-5
CAPN3ENST00000674146.1 linkc.125A>G p.Asp42Gly missense_variant Exon 8 of 12 ENSP00000501175.1 P20807-5
CAPN3ENST00000674149.1 linkc.125A>G p.Asp42Gly missense_variant Exon 7 of 11 ENSP00000501112.1 P20807-5
CAPN3ENST00000673743.1 linkc.23A>G p.Asp8Gly missense_variant Exon 7 of 11 ENSP00000500989.1 A0A669KAX6
ENSG00000258461ENST00000495723.1 linkn.*2556A>G non_coding_transcript_exon_variant Exon 22 of 26 2 ENSP00000492063.1 A0A1W2PQD3
ENSG00000258461ENST00000495723.1 linkn.*2556A>G 3_prime_UTR_variant Exon 22 of 26 2 ENSP00000492063.1 A0A1W2PQD3

Frequencies

GnomAD3 genomes
AF:
0.0000723
AC:
11
AN:
152150
Hom.:
0
Cov.:
31
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:
0.00212
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:
0.000151
AC:
38
AN:
251460
Hom.:
0
AF XY:
0.000140
AC XY:
19
AN XY:
135896
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00207
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000438
AC:
64
AN:
1461846
Hom.:
0
Cov.:
32
AF XY:
0.0000385
AC XY:
28
AN XY:
727226
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00156
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
8.99e-7
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.0000722
AC:
11
AN:
152268
Hom.:
0
Cov.:
31
AF XY:
0.0000940
AC XY:
7
AN XY:
74474
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00213
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000869
ExAC
AF:
0.000173
AC:
21
Asia WGS
AF:
0.000289
AC:
1
AN:
3478

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:15
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Autosomal recessive limb-girdle muscular dystrophy type 2A Pathogenic:9
Pathogenic, criteria provided, single submitterclinical testingMyriad Genetics, Inc.Jan 06, 2020NM_000070.2(CAPN3):c.2120A>G(D707G) is classified as pathogenic in the context of calpainopathy. Sources cited for classification include the following: PMID 25079074, 26632398, 11525884 and 27066573. Classification of NM_000070.2(CAPN3):c.2120A>G(D707G) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. -
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpDec 25, 2024This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 707 of the CAPN3 protein (p.Asp707Gly). This variant is present in population databases (rs200379491, gnomAD 0.2%). This missense change has been observed in individual(s) with autosomal recessive limb-girdle muscular dystrophy (PMID: 10567047, 11525884, 25252031, 26632398). 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: 468648). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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, criteria provided, single submitterclinical testing3billion, Medical GeneticsJan 03, 2022Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000468648, PS1_S). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least 2 similarly affected unrelated individuals(PMID: 26632398, PM3_S). A different missense change at the same codon has been reported to be associated with CAPN3 related disorder (ClinVar ID: VCV000290334, PM5_P).The variant is located in a well-established functional domain or exonic hotspot, where pathogenic variants have frequently reported (PM1_M). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.966, 3CNET: 0.862, PP3_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000148, PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
Likely pathogenic, criteria provided, single submitterclinical testingNeuroMeGen, Hospital Clinico Santiago de CompostelaOct 08, 2018- -
Pathogenic, criteria provided, single submitterclinical testingVictorian Clinical Genetics Services, Murdoch Childrens Research InstituteJul 17, 2023Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with autosomal recessive limb-girdle muscular dystrophy 1 (MIM#253600). Dominant-negative is the suggested mechanism for autosomal dominant limb-girdle muscular dystrophy 4 (MIM#618129; PMIDs: 27259757, 28881388). (I) 0108 - This gene is associated with both recessive and dominant disease. Autosomal dominant limb-girdle muscular dystrophy is associated with milder presentation and later onset (PMID: 32342993). (I) 0200 - Variant is predicted to result in a missense amino acid change from aspartic acid to glycine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 (v2: 42 heterozygotes, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported in several affected individuals, including at least one homozygote, and classified as likely pathogenic and pathogenic by diagnostic laboratories in ClinVar (Shariant; PMID: 32994280 ). (SP) 1101 - Very strong and specific phenotype match for this individual. (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Pathogenic, no assertion criteria providedclinical testingNatera, Inc.May 26, 2021- -
Pathogenic, criteria provided, single submitterresearchMedical Genetic Department, The Affiliated Hospital of Qingdao UniversityDec 01, 2020The missense variant c.2120A>G/p.(Asp707Gly) in exon 20 resulted in a single-nucleotide polymorphism (A to G) at site 2120 in the coding region of CAPN3 (NM_000070.2), which introduced an aspartic acid residue that replaced a glycine in codon 707 (Fig. 3A). This variant was previously reported in multiple (>10) homozygous or compound heterozygous patients with LGMDs (PM3-PVS), which co-segregated within a family (PP1-PM). The normal population database includes this variant; its frequency is 0.0148% (42/282854, gnomAD) (PM2); bioinformatics analysis software SIFT, PolyPhen2, and Variant Taster consistently predicted the variant to be harmful (PP3). In addition, the variant is included in ClinVar as a “pathogenic/suspected pathogenic variant.” According to available evidence, the variant is defined as pathogenic (PM3-PVS+PM2+PP1-PM+PP3) based on the 2015 ACMG guidelines for sequence variant interpretation.The WES of this patient revealed compound heterozygous variants in CAPN3, c.2120A>G/p. (Asp707Gly) in exon 20 and c.2201_2202delAT/p.(Tyr734*) in exon 21, which were inherited from his parents and absent from 200 control individuals of similar ethnic origin, indicating that these variants are the pathogenic triggers of the LGMDR1 phenotype. In summary, we observed a sporadic male case of LGMDR1 and identified two compound heterozygous variants in CAPN3, namely c.2120A>G/p. (Asp707Gly) and c.2201_2202delAT/ p.(Tyr734*)), which co-segregated with the LGMDR1 phenotypes in the proband’s family. -
Likely pathogenic, criteria provided, single submitterclinical testingNeuberg Centre For Genomic Medicine, NCGMJun 22, 2023The missense c.2120A>G (p.Asp707Gly) variant in CAPN3 gene has been reported in compound heterozygous state in multiple individuals affected with autosomal recessive Muscular dystrophy, limb-girdle (Park et. al., 2016; Park et. al., 2017). The p.Asp707Gly variant is present with allele frequency of 0.01% in gnomAD exomes database. This variant has been submitted to the ClinVar database as Pathogenic / Likely Pathogenic. The variant is located in a well-established functional domain or exonic hotspot, where pathogenic variants have frequently reported. Multiple lines of computational evidence (Polyphen - probably damaging, SIFT - damaging and MutationTaster - disease causing) predict a damaging effect on protein structure and function for this variant. The reference amino acid at this position on CAPN3 gene is predicted as as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Asp at position 707 is changed to a Gly changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Likely Pathogenic. In the absence of another reportable variant in CAPN3 gene, the molecular diagnosis is not confirmed. The above variant has also been reported in heterozygous state in father . -
Pathogenic, criteria provided, single submitterclinical testingBaylor Genetics-- -
not provided Pathogenic:3
Pathogenic, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Oct 14, 2016- -
Pathogenic, criteria provided, single submitterclinical testingGeneDxJan 27, 2022Published functional studies demonstrate no detectable protein in the muscle tissue of a patient homozygous for this variant (PMID: 10567047); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 36066420, 25525159, 27363342, 30127231, 30919934, 10567047, 26632398, 31656265, 33899113, 25252031, 25079074, 32573981, 27066573, 34323405, 11525884, 27500519, 32994280, 35314707, 28403181) -
Pathogenic, criteria provided, single submitterclinical testingRevvity Omics, RevvityFeb 08, 2019- -
Muscular dystrophy, limb-girdle, autosomal dominant 4 Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingBaylor GeneticsMar 26, 2024- -
Autosomal recessive limb-girdle muscular dystrophy type 2A;C4748295:Muscular dystrophy, limb-girdle, autosomal dominant 4 Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsJun 04, 2024- -
CAPN3-related disorder Pathogenic:1
Pathogenic, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesFeb 02, 2024The CAPN3 c.2120A>G variant is predicted to result in the amino acid substitution p.Asp707Gly. This variant has been reported with a second CAPN3 variant or in the homozygous state in individuals with limb-girdle muscular dystrophy (see, for example, Minami et al. 1999. PubMed ID: 10567047; Chae et al. 2001. PubMed ID: 11525884; Park et al. 2016. PubMed ID: 26632398). This variant is reported in 0.21% of alleles in individuals of East Asian descent in gnomAD. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.76
BayesDel_addAF
Pathogenic
0.21
D
BayesDel_noAF
Pathogenic
0.53
CADD
Pathogenic
30
DANN
Uncertain
1.0
DEOGEN2
Benign
0.11
T;.;.;D;.;.;.;.;.;.;.;.
Eigen
Pathogenic
1.0
Eigen_PC
Pathogenic
0.91
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.95
D;D;D;D;D;D;.;D;.;D;.;D
M_CAP
Pathogenic
0.52
D
MetaRNN
Benign
0.39
T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM
Pathogenic
0.97
D
MutationAssessor
Pathogenic
3.2
.;.;.;M;.;.;.;.;.;.;.;.
PrimateAI
Uncertain
0.67
T
PROVEAN
Pathogenic
-6.0
D;D;D;D;D;D;D;.;D;D;D;D
REVEL
Pathogenic
0.97
Sift
Benign
0.052
T;D;D;D;D;D;D;.;D;D;D;D
Sift4G
Uncertain
0.0070
D;D;D;D;D;D;D;D;D;D;D;D
Polyphen
1.0
.;D;D;D;.;.;.;.;.;.;.;.
Vest4
0.89
MVP
0.98
MPC
0.68
ClinPred
0.58
D
GERP RS
5.0
Varity_R
0.87
gMVP
0.74

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.

Other links and lift over

dbSNP: rs200379491; hg19: chr15-42702630; API