rs144383442

Positions:

chr15-42387779-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_StrongBP6BP7BS2

The ENST00000397163.8(CAPN3):c.525C>T(p.Asp175=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000955 in 1,614,144 control chromosomes in the GnomAD database, including 2 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 0.00062 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00099 ( 2 hom. )

Consequence

CAPN3
ENST00000397163.8 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:6

Conservation

PhyloP100: -1.93

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -10 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.51).

BP6

Variant 15-42387779-C-T is Benign according to our data. Variant chr15-42387779-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 197103.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Likely_benign=3, Uncertain_significance=3}. Variant chr15-42387779-C-T is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=-1.93 with no splicing effect.

BS2

High Homozygotes in GnomAdExome4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
CAPN3	NM_000070.3 linkuse as main transcript	c.525C>T	p.Asp175=	synonymous_variant	4/24	ENST00000397163.8	NP_000061.1
CAPN3	NM_024344.2 linkuse as main transcript	c.525C>T	p.Asp175=	synonymous_variant	4/23		NP_077320.1
CAPN3	NM_173087.2 linkuse as main transcript	c.525C>T	p.Asp175=	synonymous_variant	4/21		NP_775110.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CAPN3	ENST00000397163.8 linkuse as main transcript	c.525C>T	p.Asp175=	synonymous_variant	4/24	1	NM_000070.3	ENSP00000380349	P2	P20807-1

Frequencies

GnomAD3 genomes

AF:

0.000624

AC:

AN:

152156

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000458

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.000415

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00113

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000620

AC:

156

AN:

251452

Hom.:

AF XY:

0.000655

AC XY:

AN XY:

135890

show subpopulations

Gnomad AFR exome

AF:

0.000246

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000392

Gnomad FIN exome

AF:

0.000323

Gnomad NFE exome

AF:

0.00114

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000989

AC:

1446

AN:

1461870

Hom.:

Cov.:

AF XY:

0.000997

AC XY:

725

AN XY:

727240

show subpopulations

Gnomad4 AFR exome

AF:

0.000179

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000533

Gnomad4 FIN exome

AF:

0.000449

Gnomad4 NFE exome

AF:

0.00121

Gnomad4 OTH exome

AF:

0.000430

GnomAD4 genome

AF:

0.000624

AC:

AN:

152274

Hom.:

Cov.:

AF XY:

0.000618

AC XY:

AN XY:

74446

show subpopulations

Gnomad4 AFR

AF:

0.000120

Gnomad4 AMR

AF:

0.000458

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.000415

Gnomad4 FIN

AF:

0.000188

Gnomad4 NFE

AF:

0.00113

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.00122

Hom.:

Bravo

AF:

0.000661

EpiCase

AF:

0.000927

EpiControl

AF:

0.00119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Autosomal recessive limb-girdle muscular dystrophy type 2A

Uncertain:1Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Apr 17, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -

not provided

Uncertain:1Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 03, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2024	CAPN3: BP4, BP7 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 01, 2019	- -

Limb-girdle muscular dystrophy, recessive

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Dec 22, 2020

- -

CAPN3-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 27, 2024

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.51

CADD

Benign

6.0

DANN

Benign

0.79

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.20

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.20

Position offset: -26

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