rs1801505

Positions:

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PM1BP4_StrongBP6_Very_StrongBS2

The NM_000070.3(CAPN3):c.319G>A(p.Glu107Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00855 in 1,613,074 control chromosomes in the GnomAD database, including 93 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0067 ( 11 hom., cov: 32)

Exomes 𝑓: 0.0087 ( 82 hom. )

Consequence

CAPN3
NM_000070.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 4.16

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 -14 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 8 uncertain in NM_000070.3

BP4

Computational evidence support a benign effect (MetaRNN=0.009398013).

BP6

Variant 15-42384492-G-A is Benign according to our data. Variant chr15-42384492-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 195011.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-42384492-G-A is described in Lovd as [Likely_benign]. Variant chr15-42384492-G-A is described in Lovd as [Pathogenic]. Variant chr15-42384492-G-A is described in Lovd as [Benign].

BS2

High Homozygotes in GnomAd4 at 11 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
CAPN3	NM_000070.3 linkuse as main transcript	c.319G>A	p.Glu107Lys	missense_variant	2/24	ENST00000397163.8
CAPN3	NM_024344.2 linkuse as main transcript	c.319G>A	p.Glu107Lys	missense_variant	2/23
CAPN3	NM_173087.2 linkuse as main transcript	c.319G>A	p.Glu107Lys	missense_variant	2/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CAPN3	ENST00000397163.8 linkuse as main transcript	c.319G>A	p.Glu107Lys	missense_variant	2/24	1	NM_000070.3	P2	P20807-1

Frequencies

GnomAD3 genomes

AF:

0.00672

AC:

1022

AN:

152118

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00154

Gnomad AMI

AF:

0.0329

Gnomad AMR

AF:

0.000851

Gnomad ASJ

AF:

0.000866

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0235

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00966

Gnomad OTH

AF:

0.00239

GnomAD3 exomes

AF:

0.00853

AC:

2146

AN:

251436

Hom.:

AF XY:

0.00823

AC XY:

1118

AN XY:

135892

show subpopulations

Gnomad AFR exome

AF:

0.00154

Gnomad AMR exome

AF:

0.000838

Gnomad ASJ exome

AF:

0.000397

Gnomad EAS exome

AF:

0.000163

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.0259

Gnomad NFE exome

AF:

0.0130

Gnomad OTH exome

AF:

0.00782

GnomAD4 exome

AF:

0.00874

AC:

12767

AN:

1460838

Hom.:

Cov.:

AF XY:

0.00847

AC XY:

6158

AN XY:

726816

show subpopulations

Gnomad4 AFR exome

AF:

0.00108

Gnomad4 AMR exome

AF:

0.000962

Gnomad4 ASJ exome

AF:

0.000230

Gnomad4 EAS exome

AF:

0.000302

Gnomad4 SAS exome

AF:

0.0000464

Gnomad4 FIN exome

AF:

0.0252

Gnomad4 NFE exome

AF:

0.00985

Gnomad4 OTH exome

AF:

0.00616

GnomAD4 genome

AF:

0.00671

AC:

1022

AN:

152236

Hom.:

Cov.:

AF XY:

0.00674

AC XY:

502

AN XY:

74436

show subpopulations

Gnomad4 AFR

AF:

0.00154

Gnomad4 AMR

AF:

0.000850

Gnomad4 ASJ

AF:

0.000866

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0235

Gnomad4 NFE

AF:

0.00966

Gnomad4 OTH

AF:

0.00237

Alfa

AF:

0.00800

Hom.:

Bravo

AF:

0.00481

TwinsUK

AF:

0.00755

AC:

ALSPAC

AF:

0.00960

AC:

ESP6500AA

AF:

0.00204

AC:

ESP6500EA

AF:

0.00872

AC:

ExAC

AF:

0.0104

AC:

1266

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 25, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 06, 2017	p.Glu107Lys in exon 2 of CAPN3: This variant is not expected to have clinical si gnificance because it has been identified in 2.8% (188/66736) of European (Finni sh) chromosomes including 2 homozygotes by the Exome Aggregation Consortium (ExA C, http://exac.broadinstitute.org; dbSNP rs150616566) -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 25, 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. -

Autosomal recessive limb-girdle muscular dystrophy type 2A

Benign:3

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 13, 2020	- -
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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

not provided

Benign:3

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	CAPN3: BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 05, 2017	- -

Autosomal recessive limb-girdle muscular dystrophy type 2A;C4748295:Muscular dystrophy, limb-girdle, autosomal dominant 4

Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 18, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.075

BayesDel_noAF

Uncertain

0.13

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.10

T;.;.;T

Eigen

Benign

-0.49

Eigen_PC

Benign

-0.28

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.75

T;T;T;T

MetaRNN

Benign

0.0094

T;T;T;T

MetaSVM

Uncertain

0.059

MutationAssessor

Benign

0.93

.;L;L;L

MutationTaster

Benign

1.0

D;D;D;D;D

PrimateAI

Uncertain

0.61

PROVEAN

Benign

-1.3

N;N;N;N

REVEL

Uncertain

0.59

Sift

Benign

0.69

T;T;T;T

Sift4G

Benign

0.83

T;T;T;T

Polyphen

0.0060, 0.011, 0.014

.;B;B;B

Vest4

0.34

MPC

0.18

ClinPred

0.0092

GERP RS

3.6

Varity_R

0.26

gMVP

0.68

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