rs28364543

chr15-42411339-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Moderate BP6 BP7 BS1 BS2

The NM_000070.3(CAPN3):c.2433T>C(p.Val811=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00197 in 1,613,906 control chromosomes in the GnomAD database, including 60 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.011 (33 hom., cov: 30)
  • Exomes 𝑓: 0.0011 (27 hom.)
• Consequence: CAPN3 NM_000070.3 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:7
• Conservation: PhyloP100: 0.435

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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.38).
• BP6: Variant 15-42411339-T-C is Benign according to our data. Variant chr15-42411339-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 166793.We mark this variant Likely_benign, oryginal submissions are: {Benign=5, Uncertain_significance=1, Likely_benign=1}. Variant chr15-42411339-T-C is described in Lovd as [Likely_benign]. Variant chr15-42411339-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.435 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0107 (1622/152172) while in subpopulation AFR AF= 0.0377 (1563/41506). AF 95% confidence interval is 0.0361. There are 33 homozygotes in gnomad4. There are 737 alleles in male gnomad4 subpopulation. Median coverage is 30. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 32 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CAPN3	NM_000070.3	c.2433T>C	p.Val811=	synonymous_variant	23/24	ENST00000397163.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CAPN3	ENST00000397163.8	c.2433T>C	p.Val811=	synonymous_variant	23/24	1	NM_000070.3	P2

Frequencies

GnomAD3 genomes AF: 0.0106 AC: 1616 AN: 152054 Hom.: 32 Cov.: 30

Gnomad AFR AF: 0.0376

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00216

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00813

GnomAD3 exomes AF: 0.00268 AC: 675 AN: 251438 Hom.: 12 AF XY: 0.00203 AC XY: 276 AN XY: 135892

Gnomad AFR exome AF: 0.0388

Gnomad AMR exome AF: 0.000781

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000196

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000879

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.00106 AC: 1555 AN: 1461734 Hom.: 27 Cov.: 32 AF XY: 0.000924 AC XY: 672 AN XY: 727184

Gnomad4 AFR exome AF: 0.0398

Gnomad4 AMR exome AF: 0.00105

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000139

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000270

Gnomad4 OTH exome AF: 0.00212

GnomAD4 genome AF: 0.0107 AC: 1622 AN: 152172 Hom.: 33 Cov.: 30 AF XY: 0.00991 AC XY: 737 AN XY: 74406

Gnomad4 AFR AF: 0.0377

Gnomad4 AMR AF: 0.00216

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00805

Alfa AF: 0.00275 Hom.: 5

Bravo AF: 0.0121

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000237

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:7

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 05, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 14, 2014	- -

Autosomal recessive limb-girdle muscular dystrophy type 2A Benign:3

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

Limb-Girdle Muscular Dystrophy, Recessive Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Dec 27, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.38
Cadd	Benign	9.2
Dann	Benign	0.78

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: rs28364543; hg19: chr15-42703537;