rs760891133

Positions:

• chr15-42410982-A-C
• chr15-42410982-A-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP7

The NM_000070.3(CAPN3):​c.2362A>C​(p.Arg788Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Synonymous variant affecting the same amino acid position (i.e. R788H?) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: CAPN3 NM_000070.3 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.850

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_benign. Variant got -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.4).
• BP7: Synonymous conserved (PhyloP=0.85 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CAPN3	NM_000070.3	c.2362A>C	p.Arg788Arg	synonymous_variant	22/24	ENST00000397163.8	NP_000061.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CAPN3	ENST00000397163.8	c.2362A>C	p.Arg788Arg	synonymous_variant	22/24	1	NM_000070.3	ENSP00000380349.3
CAPN3	ENST00000673886.1	c.367A>C	p.Arg123Arg	synonymous_variant	9/11			ENSP00000501155.1
CAPN3	ENST00000673928.1	c.367A>C	p.Arg123Arg	synonymous_variant	9/11			ENSP00000501099.1
CAPN3	ENST00000674146.1	c.367A>C	p.Arg123Arg	synonymous_variant	10/12			ENSP00000501175.1
CAPN3	ENST00000674149.1	c.367A>C	p.Arg123Arg	synonymous_variant	9/11			ENSP00000501112.1
CAPN3	ENST00000673743.1	c.265A>C	p.Arg89Arg	synonymous_variant	9/11			ENSP00000500989.1
ENSG00000258461	ENST00000495723.1	n.*2798A>C		non_coding_transcript_exon_variant	24/26	2		ENSP00000492063.1
ENSG00000258461	ENST00000495723.1	n.*2798A>C		3_prime_UTR_variant	24/26	2		ENSP00000492063.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

Bravo AF: 0.0000680

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 13, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.40
CADD	Benign	10
DANN	Benign	0.89

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs760891133; hg19: chr15-42703180;