NM_000070.3:c.2362A>C

Variant names:

• chr15-42410982-A-C
• rs760891133
• NM_000070.3:c.2362A>C

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Moderate BP6_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. R788R) has been classified as Likely benign.

• 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
• Publications: 3 publications found

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]

CAPN3 Gene-Disease associations (from GenCC):

• autosomal recessive limb-girdle muscular dystrophy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• autosomal recessive limb-girdle muscular dystrophy type 2A

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Myriad Women’s Health, Labcorp Genetics (formerly Invitae)
• muscular dystrophy, limb-girdle, autosomal dominant 4

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• muscular dystrophy, limb-girdle, autosomal dominant

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ENSG00000258461 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.4).
• BP6: Variant 15-42410982-A-C is Benign according to our data. Variant chr15-42410982-A-C is described in ClinVar as Likely_benign. ClinVar VariationId is 468649.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.85 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000070.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CAPN3	NM_000070.3	MANE Select	c.2362A>C	p.Arg788Arg	synonymous	Exon 22 of 24	NP_000061.1
	CAPN3	NM_024344.2		c.2344A>C	p.Arg782Arg	synonymous	Exon 21 of 23	NP_077320.1
	CAPN3	NM_173087.2		c.2086A>C	p.Arg696Arg	synonymous	Exon 19 of 21	NP_775110.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CAPN3	ENST00000397163.8	TSL:1 MANE Select	c.2362A>C	p.Arg788Arg	synonymous	Exon 22 of 24	ENSP00000380349.3
	CAPN3	ENST00000357568.8	TSL:1	c.2344A>C	p.Arg782Arg	synonymous	Exon 21 of 23	ENSP00000350181.3
	CAPN3	ENST00000349748.8	TSL:1	c.2086A>C	p.Arg696Arg	synonymous	Exon 19 of 21	ENSP00000183936.4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

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

Oct 06, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.40
CADD	Benign	10
DANN	Benign	0.89
PhyloP100		0.85

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

Other links and lift over

dbSNP: rs760891133; hg19: chr15-42703180;