15-42410449-A-T

Position:

• chr15-42410449-A-T

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.2137A>T​(p.Asn713Tyr) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 31)
• Consequence: CAPN3 NM_000070.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.85

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 domain EF-hand 2 (size 33) in uniprot entity CAN3_HUMAN there are 29 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, 0.887

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CAPN3	NM_000070.3	c.2137A>T	p.Asn713Tyr	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.2137A>T	p.Asn713Tyr	missense_variant	20/24	1	NM_000070.3	ENSP00000380349.3
CAPN3	ENST00000673886.1	c.142A>T	p.Asn48Tyr	missense_variant	7/11			ENSP00000501155.1
CAPN3	ENST00000673928.1	c.142A>T	p.Asn48Tyr	missense_variant	7/11			ENSP00000501099.1
CAPN3	ENST00000674146.1	c.142A>T	p.Asn48Tyr	missense_variant	8/12			ENSP00000501175.1
CAPN3	ENST00000674149.1	c.142A>T	p.Asn48Tyr	missense_variant	7/11			ENSP00000501112.1
CAPN3	ENST00000673743.1	c.40A>T	p.Asn14Tyr	missense_variant	7/11			ENSP00000500989.1
ENSG00000258461	ENST00000495723.1	n.*2573A>T		non_coding_transcript_exon_variant	22/26	2		ENSP00000492063.1
ENSG00000258461	ENST00000495723.1	n.*2573A>T		3_prime_UTR_variant	22/26	2		ENSP00000492063.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.16
CADD	Uncertain	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.16	T;.;.;D;.;.;.;.;.;.;.;.
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.95	D;D;D;D;D;D;.;D;.;D;.;D
M_CAP	Pathogenic	0.39	D
MetaRNN	Pathogenic	0.89	D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.55	D
MutationAssessor	Pathogenic	2.9	.;.;.;M;.;.;.;.;.;.;.;.
PrimateAI	Uncertain	0.67	T
PROVEAN	Uncertain	-4.2	.;D;D;D;D;D;D;.;D;D;D;D
REVEL	Pathogenic	0.84
Sift	Uncertain	0.0030	.;D;D;D;D;D;D;.;D;D;D;D
Sift4G	Uncertain	0.0050	D;D;D;D;D;D;D;D;D;D;D;D
Polyphen		1.0	.;D;D;D;.;.;.;.;.;.;.;.
Vest4		0.72
MutPred		0.58		.;.;.;Loss of disorder (P = 0.0719);.;.;.;.;.;.;.;.;
MVP		0.92
MPC		0.69
ClinPred		1.0	D
GERP RS		4.7
Varity_R		0.66
gMVP		0.79

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs748363488; hg19: chr15-42702647;