chr15-42384491-C-T

Position:

chr15-42384491-C-T

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_ModerateBP6_Very_StrongBP7BS2

The ENST00000397163.8(CAPN3):c.318C>T(p.Cys106=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00573 in 1,612,482 control chromosomes in the GnomAD database, including 34 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0049 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0058 ( 34 hom. )

Consequence

CAPN3
ENST00000397163.8 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: -0.304

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -15 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.31).

BP6

Variant 15-42384491-C-T is Benign according to our data. Variant chr15-42384491-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 92416.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-42384491-C-T is described in Lovd as [Likely_benign]. Variant chr15-42384491-C-T is described in Lovd as [Benign]. Variant chr15-42384491-C-T is described in Lovd as [Pathogenic].

BP7

Synonymous conserved (PhyloP=-0.304 with no splicing effect.

BS2

High Homozygotes in GnomAdExome4 at 34 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
CAPN3	NM_000070.3 linkuse as main transcript	c.318C>T	p.Cys106=	synonymous_variant	2/24	ENST00000397163.8	NP_000061.1
CAPN3	NM_024344.2 linkuse as main transcript	c.318C>T	p.Cys106=	synonymous_variant	2/23		NP_077320.1
CAPN3	NM_173087.2 linkuse as main transcript	c.318C>T	p.Cys106=	synonymous_variant	2/21		NP_775110.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CAPN3	ENST00000397163.8 linkuse as main transcript	c.318C>T	p.Cys106=	synonymous_variant	2/24	1	NM_000070.3	ENSP00000380349	P2	P20807-1

Frequencies

GnomAD3 genomes

AF:

0.00488

AC:

743

AN:

152136

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00138

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00628

Gnomad ASJ

AF:

0.00404

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00166

Gnomad FIN

AF:

0.00292

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00763

Gnomad OTH

AF:

0.00766

GnomAD3 exomes

AF:

0.00470

AC:

1182

AN:

251426

Hom.:

AF XY:

0.00475

AC XY:

646

AN XY:

135878

show subpopulations

Gnomad AFR exome

AF:

0.00111

Gnomad AMR exome

AF:

0.00506

Gnomad ASJ exome

AF:

0.00298

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00118

Gnomad FIN exome

AF:

0.00282

Gnomad NFE exome

AF:

0.00725

Gnomad OTH exome

AF:

0.00603

GnomAD4 exome

AF:

0.00582

AC:

8494

AN:

1460228

Hom.:

Cov.:

AF XY:

0.00570

AC XY:

4142

AN XY:

726566

show subpopulations

Gnomad4 AFR exome

AF:

0.000987

Gnomad4 AMR exome

AF:

0.00532

Gnomad4 ASJ exome

AF:

0.00283

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.00165

Gnomad4 FIN exome

AF:

0.00275

Gnomad4 NFE exome

AF:

0.00673

Gnomad4 OTH exome

AF:

0.00585

GnomAD4 genome

AF:

0.00487

AC:

742

AN:

152254

Hom.:

Cov.:

AF XY:

0.00450

AC XY:

335

AN XY:

74460

show subpopulations

Gnomad4 AFR

AF:

0.00137

Gnomad4 AMR

AF:

0.00628

Gnomad4 ASJ

AF:

0.00404

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00166

Gnomad4 FIN

AF:

0.00292

Gnomad4 NFE

AF:

0.00762

Gnomad4 OTH

AF:

0.00758

Alfa

AF:

0.00622

Hom.:

Bravo

AF:

0.00533

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00971

EpiControl

AF:

0.00877

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2020	This variant is associated with the following publications: (PMID: 10330340, 16141003) -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Oct 26, 2018	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	CAPN3: BP4, BP7, BS2 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 21, 2014	- -
Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 13, 2015	p.Cys106Cys in exon 2 of CAPN3: This variant is not expected to have clinical si gnificance because it does not alter an amino acid residue and is not located wi thin the splice consensus sequence. It has been identified in 0.9% (78/8598) of European American chromosomes from a broad population by the NHLBI Exome Sequenc ing Project (http://evs.gs.washington.edu/EVS; dbSNP rs117609395). -

Autosomal recessive limb-girdle muscular dystrophy type 2A

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Dec 03, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.31

CADD

Benign

2.3

DANN

Benign

0.65

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over