15-42410432-A-G

Position:

• chr15-42410432-A-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 13P and 1B. PM1 PM5 PP3 PP5_Very_Strong BP4

The ENST00000397163.8(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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D707H) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000072 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000044 (0 hom.)
• Consequence: CAPN3 ENST00000397163.8 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:14
• Conservation: PhyloP100: 7.48

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]

ENSG00000258461 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 12 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, 8 uncertain in ENST00000397163.8
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr15-42410431-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 290334.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, Uncertain_significance=1}.
• 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/exons	MANE	Protein	UniProt
CAPN3	NM_000070.3	c.2120A>G	p.Asp707Gly	missense_variant	20/24	ENST00000397163.8	NP_000061.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CAPN3	ENST00000397163.8	c.2120A>G	p.Asp707Gly	missense_variant	20/24	1	NM_000070.3	ENSP00000380349.3
CAPN3	ENST00000673886.1	c.125A>G	p.Asp42Gly	missense_variant	7/11			ENSP00000501155.1
CAPN3	ENST00000673928.1	c.125A>G	p.Asp42Gly	missense_variant	7/11			ENSP00000501099.1
CAPN3	ENST00000674146.1	c.125A>G	p.Asp42Gly	missense_variant	8/12			ENSP00000501175.1
CAPN3	ENST00000674149.1	c.125A>G	p.Asp42Gly	missense_variant	7/11			ENSP00000501112.1
CAPN3	ENST00000673743.1	c.23A>G	p.Asp8Gly	missense_variant	7/11			ENSP00000500989.1
ENSG00000258461	ENST00000495723.1	n.*2556A>G		non_coding_transcript_exon_variant	22/26	2		ENSP00000492063.1
ENSG00000258461	ENST00000495723.1	n.*2556A>G		3_prime_UTR_variant	22/26	2		ENSP00000492063.1

Frequencies

GnomAD3 genomes AF: 0.0000723 AC: 11 AN: 152150 Hom.: 0 Cov.: 31

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

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

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

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:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal recessive limb-girdle muscular dystrophy type 2A Pathogenic:8

Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Jan 06, 2020	NM_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, no assertion criteria provided	clinical testing	Natera, Inc.	May 26, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	This 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). 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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	NeuroMeGen, Hospital Clinico Santiago de Compostela	Oct 08, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	-	- -
Pathogenic, criteria provided, single submitter	research	Medical Genetic Department, The Affiliated Hospital of Qingdao University	Dec 01, 2020	The 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. -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Jan 03, 2022	Same 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Jul 17, 2023	Based 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 -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Feb 08, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 14, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 27, 2022	Published 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) -

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

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 26, 2024

- -

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 16, 2021

- -

CAPN3-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 02, 2024

The 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;.;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D
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

Other links and lift over

dbSNP: rs200379491; hg19: chr15-42702630;