rs1555422962

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, single submitter U:1
• 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]

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	UniProt
CAPN3	NM_000070.3	c.1979A>G	p.Gln660Arg	missense_variant	17/24	ENST00000397163.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CAPN3	ENST00000397163.8	c.1979A>G	p.Gln660Arg	missense_variant	17/24	1	NM_000070.3	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Uncertain significance, criteria provided, single submitter

clinical testing

Counsyl

May 01, 2018

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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
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D
PrimateAI	Benign	0.43	T
REVEL	Pathogenic	0.79
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;