rs727503838

chr15-42399652-G-Cchr15-42399652-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP3_Strong PP5

The NM_000070.3(CAPN3):c.1354G>C(p.Asp452His) variant causes a missense, splice region 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. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D452G) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: CAPN3 NM_000070.3 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 10.0

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 9 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_000070.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 15-42399652-G-C is Pathogenic according to our data. Variant chr15-42399652-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 553345.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}. Variant chr15-42399652-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CAPN3	NM_000070.3	c.1354G>C	p.Asp452His	missense_variant, splice_region_variant	10/24	ENST00000397163.8
CAPN3	NM_024344.2	c.1354G>C	p.Asp452His	missense_variant, splice_region_variant	10/23
CAPN3	NM_173087.2	c.1210G>C	p.Asp404His	missense_variant, splice_region_variant	9/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CAPN3	ENST00000397163.8	c.1354G>C	p.Asp452His	missense_variant, splice_region_variant	10/24	1	NM_000070.3	P2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Muscular dystrophy, limb-girdle, autosomal dominant 4 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Jun 15, 2022

- -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Counsyl

Aug 22, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.70
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.37
Cadd	Pathogenic	36
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.59	D;.;.;D
Eigen	Pathogenic	0.97
Eigen_PC	Pathogenic	0.93
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.88	D;D;D;D
M_CAP	Benign	0.080	D
MetaRNN	Pathogenic	0.95	D;D;D;D
MetaSVM	Uncertain	0.78	D
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Pathogenic	0.88	D
REVEL	Pathogenic	0.88
Sift4G	Uncertain	0.042	D;D;D;D
Polyphen		0.99, 0.99	.;D;D;D
Vest4		0.76
MutPred		0.92		.;Gain of methylation at R448 (P = 0.0741);.;Gain of methylation at R448 (P = 0.0741);
MVP		0.97
MPC		0.64
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.71
gMVP		0.81

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.62		Position offset: -40
DS_DL_spliceai		0.99		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs727503838; hg19: chr15-42691850;