15-42392678-G-C

Variant names:

• chr15-42392678-G-C
• rs1085307995
• NM_000070.3:c.985G>C

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PS1_Very_Strong PM1 PM2 PP3_Strong PP5_Moderate

The NM_000070.3(CAPN3):​c.985G>C​(p.Gly329Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G329A) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CAPN3 NM_000070.3 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2 U:1
• Conservation: PhyloP100: 4.78
• Publications: 3 publications found

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

ENSG00000258461 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PS1: Transcript NM_000070.3 (CAPN3) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 427161
• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_000070.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.969
• PP5: Variant 15-42392678-G-C is Pathogenic according to our data. Variant chr15-42392678-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 553758.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CAPN3	NM_000070.3	c.985G>C	p.Gly329Arg	missense_variant	Exon 7 of 24	ENST00000397163.8	NP_000061.1
CAPN3	NM_024344.2	c.985G>C	p.Gly329Arg	missense_variant	Exon 7 of 23		NP_077320.1
CAPN3	NM_173087.2	c.841G>C	p.Gly281Arg	missense_variant	Exon 6 of 21		NP_775110.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CAPN3	ENST00000397163.8	c.985G>C	p.Gly329Arg	missense_variant	Exon 7 of 24	1	NM_000070.3	ENSP00000380349.3
ENSG00000258461	ENST00000495723.1	n.*781G>C		non_coding_transcript_exon_variant	Exon 11 of 26	2		ENSP00000492063.1
ENSG00000258461	ENST00000495723.1	n.*781G>C		3_prime_UTR_variant	Exon 11 of 26	2		ENSP00000492063.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Autosomal recessive limb-girdle muscular dystrophy type 2A Pathogenic:1 Uncertain:1

May 30, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. A different variant (c.985G>A) giving rise to the same protein effect observed here (p.Gly329Arg) has been reported in an individual affected with limb-girdle muscular dystrophy (PMID: 28915917, 16627476, Invitae), indicating that this residue may be critical for protein function. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with CAPN3-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with arginine at codon 329 of the CAPN3 protein (p.Gly329Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. -

Sep 06, 2017

Counsyl

Significance: Uncertain significance

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. -

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

Mar 15, 2023

Baylor Genetics

Significance: Likely pathogenic

Review Status: flagged submission

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.66	D;.;.;D
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.94	D;D;D;D
M_CAP	Pathogenic	0.66	D
MetaRNN	Pathogenic	0.97	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.1	.;M;.;M
PhyloP100		4.8
PrimateAI	Uncertain	0.67	T
PROVEAN	Uncertain	-3.5	.;D;D;D
REVEL	Pathogenic	0.86
Sift	Uncertain	0.018	.;D;T;D
Sift4G	Uncertain	0.053	T;D;D;D
Polyphen		1.0	.;D;D;D
Vest4		0.85
MutPred		0.83		.;Gain of MoRF binding (P = 0.0064);.;Gain of MoRF binding (P = 0.0064);
MVP		0.96
MPC		0.69
ClinPred		1.0	D
GERP RS		4.4
Varity_R		0.97
gMVP		0.94

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs1085307995; hg19: chr15-42684876;