rs1555422962

Positions:

• chr15-42409367-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP3_Moderate

The NM_000070.3(CAPN3):​c.1979A>G​(p.Gln660Arg) variant causes a missense change involving the alteration of a conserved nucleotide. 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 Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CAPN3 NM_000070.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 9.30

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a helix (size 8) in uniprot entity CAN3_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_000070.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.903

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CAPN3	NM_000070.3	c.1979A>G	p.Gln660Arg	missense_variant	17/24	ENST00000397163.8	NP_000061.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CAPN3	ENST00000397163.8	c.1979A>G	p.Gln660Arg	missense_variant	17/24	1	NM_000070.3	ENSP00000380349.3
CAPN3	ENST00000673886	c.-17A>G		5_prime_UTR_variant	4/11			ENSP00000501155.1
CAPN3	ENST00000673928	c.-17A>G		5_prime_UTR_variant	4/11			ENSP00000501099.1
CAPN3	ENST00000674146	c.-17A>G		5_prime_UTR_variant	5/12			ENSP00000501175.1
CAPN3	ENST00000674149	c.-17A>G		5_prime_UTR_variant	4/11			ENSP00000501112.1
CAPN3	ENST00000673743	c.-114A>G		5_prime_UTR_variant	4/11			ENSP00000500989.1
ENSG00000258461	ENST00000495723.1	n.*2415A>G		non_coding_transcript_exon_variant	19/26	2		ENSP00000492063.1
ENSG00000258461	ENST00000495723.1	n.*2415A>G		3_prime_UTR_variant	19/26	2		ENSP00000492063.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

May 31, 2024

Variant summary: CAPN3 c.1979A>G (p.Gln660Arg) results in a conservative amino acid change located in the Calpain-3, penta-EF-hand domain (IPR029531) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 251340 control chromosomes (gnomAD). c.1979A>G has been reported in the literature in individuals affected with Limb-Girdle Muscular Dystrophy, Autosomal Recessive (Saenz_2005, Krahn_2006, Senz_2008). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 32668095, 16650086, 15689361, 19015733). ClinVar contains an entry for this variant (Variation ID: 558137). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Counsyl

May 01, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.22
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.053	T;.;.;T;.;.;.
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.83	T;T;T;T;T;T;D
M_CAP	Uncertain	0.21	D
MetaRNN	Pathogenic	0.90	D;D;D;D;D;D;D
MetaSVM	Uncertain	0.74	D
MutationAssessor	Uncertain	2.4	.;.;.;M;.;.;.
PrimateAI	Benign	0.43	T
PROVEAN	Uncertain	-2.5	.;D;D;N;D;D;D
REVEL	Pathogenic	0.79
Sift	Benign	0.088	.;T;T;T;D;D;D
Sift4G	Benign	0.23	T;T;T;T;T;T;D
Polyphen		0.72, 0.25, 0.60	.;P;B;P;.;.;.
Vest4		0.87
MutPred		0.77		.;.;.;Gain of catalytic residue at Q660 (P = 0.0375);.;.;.;
MVP		0.95
MPC		0.39
ClinPred		0.98	D
GERP RS		5.0
Varity_R		0.42
gMVP		0.45

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

LitVar

Other links and lift over

dbSNP: rs1555422962; hg19: chr15-42701565;