15-42409951-G-C

Variant names:

• chr15-42409951-G-C
• rs140425651
• NM_000070.3:c.2071G>C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PP3_Moderate

The NM_000070.3(CAPN3):​c.2071G>C​(p.Gly691Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000685 in 1,460,174 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 Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: CAPN3 NM_000070.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 8.11

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 Uncertain_significance. Variant got 2 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.867

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CAPN3	NM_000070.3	c.2071G>C	p.Gly691Arg	missense_variant	Exon 19 of 24	ENST00000397163.8	NP_000061.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CAPN3	ENST00000397163.8	c.2071G>C	p.Gly691Arg	missense_variant	Exon 19 of 24	1	NM_000070.3	ENSP00000380349.3
CAPN3	ENST00000673886.1	c.76G>C	p.Gly26Arg	missense_variant	Exon 6 of 11			ENSP00000501155.1
CAPN3	ENST00000673928.1	c.76G>C	p.Gly26Arg	missense_variant	Exon 6 of 11			ENSP00000501099.1
CAPN3	ENST00000674146.1	c.76G>C	p.Gly26Arg	missense_variant	Exon 7 of 12			ENSP00000501175.1
CAPN3	ENST00000674149.1	c.76G>C	p.Gly26Arg	missense_variant	Exon 6 of 11			ENSP00000501112.1
CAPN3	ENST00000673743	c.-27G>C		5_prime_UTR_variant	Exon 6 of 11			ENSP00000500989.1
ENSG00000258461	ENST00000495723.1	n.*2507G>C		non_coding_transcript_exon_variant	Exon 21 of 26	2		ENSP00000492063.1
ENSG00000258461	ENST00000495723.1	n.*2507G>C		3_prime_UTR_variant	Exon 21 of 26	2		ENSP00000492063.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000685 AC: 10 AN: 1460174 Hom.: 0 Cov.: 34 AF XY: 0.00000551 AC XY: 4 AN XY: 726338

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: 0.00000809

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 15, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Apr 17, 2020

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.81
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.47
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.083	T;.;.;D;.;.;.;.;.;.;.;.
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D;D;.;D;.;D;.;D
M_CAP	Pathogenic	0.33	D
MetaRNN	Pathogenic	0.87	D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.94	D
MutationAssessor	Uncertain	2.4	.;.;.;M;.;.;.;.;.;.;.;.
PrimateAI	Uncertain	0.63	T
PROVEAN	Pathogenic	-5.3	.;D;D;D;D;D;D;.;D;D;D;D
REVEL	Pathogenic	0.91
Sift	Uncertain	0.022	.;D;D;D;D;D;D;.;D;D;D;D
Sift4G	Uncertain	0.010	D;D;D;D;D;D;D;D;D;D;D;D
Polyphen		1.0	.;D;D;D;.;.;.;.;.;.;.;.
Vest4		0.88
MutPred		0.61		.;.;.;Gain of MoRF binding (P = 0.0314);.;.;.;.;.;.;.;.;
MVP		1.0
MPC		0.62
ClinPred		0.99	D
GERP RS		4.8
Varity_R		0.55
gMVP		0.75

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs140425651; hg19: chr15-42702149;