2-240596709-A-G

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_023083.4(CAPN10):c.1510A>G(p.Thr504Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.158 in 1,563,144 control chromosomes in the GnomAD database, including 20,757 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.13 ( 1449 hom., cov: 34)

Exomes 𝑓: 0.16 ( 19308 hom. )

Consequence

CAPN10
NM_023083.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -1.09

Variant links:

Genes affected

CAPN10 (HGNC:1477): (calpain 10) Calpains represent a ubiquitous, well-conserved family of calcium-dependent cysteine proteases. The calpain proteins are heterodimers consisting of an invariant small subunit and variable large subunits. The large catalytic subunit has four domains: domain I, the N-terminal regulatory domain that is processed upon calpain activation; domain II, the protease domain; domain III, a linker domain of unknown function; and domain IV, the calmodulin-like calcium-binding domain. This gene encodes a large subunit. It is an atypical calpain in that it lacks the calmodulin-like calcium-binding domain and instead has a divergent C-terminal domain. It is similar in organization to calpains 5 and 6. This gene is associated with type 2 or non-insulin-dependent diabetes mellitus (NIDDM), and is located within the NIDDM1 region. Multiple alternative transcript variants have been described for this gene. [provided by RefSeq, Sep 2010]

CAPN10 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0023303628).

BP6

Variant 2-240596709-A-G is Benign according to our data. Variant chr2-240596709-A-G is described in ClinVar as [Benign]. Clinvar id is 1296539.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.184 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CAPN10	NM_023083.4 link	c.1510A>G	p.Thr504Ala	missense_variant	Exon 9 of 12	ENST00000391984.7	NP_075571.2	Q9HC96-1
CAPN10	NM_023085.4 link	c.1279-1179A>G		intron_variant	Intron 7 of 9		NP_075573.3	Q9HC96-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CAPN10	ENST00000391984.7 link	c.1510A>G	p.Thr504Ala	missense_variant	Exon 9 of 12	1	NM_023083.4	ENSP00000375844.2		Q9HC96-1

Frequencies

GnomAD3 genomes

AF:

0.126

AC:

19132

AN:

151768

Hom.:

1448

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0472

Gnomad AMI

AF:

0.152

Gnomad AMR

AF:

0.0995

Gnomad ASJ

AF:

0.0837

Gnomad EAS

AF:

0.0983

Gnomad SAS

AF:

0.194

Gnomad FIN

AF:

0.190

Gnomad MID

AF:

0.120

Gnomad NFE

AF:

0.169

Gnomad OTH

AF:

0.119

GnomAD3 exomes

AF:

0.143

AC:

29630

AN:

206792

Hom.:

2435

AF XY:

0.149

AC XY:

16602

AN XY:

111398

show subpopulations

Gnomad AFR exome

AF:

0.0441

Gnomad AMR exome

AF:

0.0797

Gnomad ASJ exome

AF:

0.0887

Gnomad EAS exome

AF:

0.0973

Gnomad SAS exome

AF:

0.196

Gnomad FIN exome

AF:

0.190

Gnomad NFE exome

AF:

0.168

Gnomad OTH exome

AF:

0.149

GnomAD4 exome

AF:

0.162

AC:

228210

AN:

1411258

Hom.:

19308

Cov.:

AF XY:

0.162

AC XY:

112993

AN XY:

696228

show subpopulations

Gnomad4 AFR exome

AF:

0.0412

Gnomad4 AMR exome

AF:

0.0816

Gnomad4 ASJ exome

AF:

0.0901

Gnomad4 EAS exome

AF:

0.0916

Gnomad4 SAS exome

AF:

0.191

Gnomad4 FIN exome

AF:

0.191

Gnomad4 NFE exome

AF:

0.169

Gnomad4 OTH exome

AF:

0.151

GnomAD4 genome

AF:

0.126

AC:

19142

AN:

151886

Hom.:

1449

Cov.:

AF XY:

0.127

AC XY:

9452

AN XY:

74266

show subpopulations

Gnomad4 AFR

AF:

0.0473

Gnomad4 AMR

AF:

0.0995

Gnomad4 ASJ

AF:

0.0837

Gnomad4 EAS

AF:

0.0985

Gnomad4 SAS

AF:

0.195

Gnomad4 FIN

AF:

0.190

Gnomad4 NFE

AF:

0.169

Gnomad4 OTH

AF:

0.119

Alfa

AF:

0.143

Hom.:

971

Bravo

AF:

0.114

TwinsUK

AF:

0.167

AC:

619

ALSPAC

AF:

0.176

AC:

680

ESP6500AA

AF:

0.0458

AC:

174

ESP6500EA

AF:

0.156

AC:

1278

ExAC

AF:

0.140

AC:

16850

Asia WGS

AF:

0.147

AC:

514

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Sep 29, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 14741193) -

CAPN10-related disorder

Benign:1

Oct 17, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as 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

AlphaMissense

Benign

0.054

BayesDel_addAF

Benign

-0.67

BayesDel_noAF

Benign

-0.59

CADD

Benign

0.015

DANN

Benign

0.24

DEOGEN2

Benign

0.074

T;.

Eigen

Benign

-2.2

Eigen_PC

Benign

-2.1

FATHMM_MKL

Benign

0.0047

LIST_S2

Benign

0.22

T;T

MetaRNN

Benign

0.0023

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.77

N;.

PrimateAI

Benign

0.36

PROVEAN

Benign

0.45

N;N

REVEL

Benign

0.22

Sift

Benign

0.82

T;T

Sift4G

Benign

0.99

T;T

Polyphen

0.0

B;B

Vest4

0.031

MPC

0.34

ClinPred

0.000014

GERP RS

-3.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.026

gMVP

0.21

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