2-240592060-C-A

Position:

chr2-240592060-C-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_023083.4(CAPN10):c.598C>A(p.Pro200Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00221 in 1,609,804 control chromosomes in the GnomAD database, including 48 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: 𝑓 0.0021 ( 7 hom., cov: 34)

Exomes 𝑓: 0.0022 ( 41 hom. )

Consequence

CAPN10
NM_023083.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 1.13

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=0.0033745766).

BP6

Variant 2-240592060-C-A is Benign according to our data. Variant chr2-240592060-C-A is described in ClinVar as [Benign]. Clinvar id is 726946.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-240592060-C-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00211 (322/152322) while in subpopulation EAS AF= 0.0387 (200/5168). AF 95% confidence interval is 0.0343. There are 7 homozygotes in gnomad4. There are 182 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CAPN10	NM_023083.4 linkuse as main transcript	c.598C>A	p.Pro200Thr	missense_variant	4/12	ENST00000391984.7	NP_075571.2
CAPN10	NM_023085.4 linkuse as main transcript	c.598C>A	p.Pro200Thr	missense_variant	4/10		NP_075573.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CAPN10	ENST00000391984.7 linkuse as main transcript	c.598C>A	p.Pro200Thr	missense_variant	4/12	1	NM_023083.4	ENSP00000375844	P1	Q9HC96-1

Frequencies

GnomAD3 genomes

AF:

0.00213

AC:

324

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000579

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00144

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0388

Gnomad SAS

AF:

0.00248

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00637

Gnomad NFE

AF:

0.000794

Gnomad OTH

AF:

0.00431

GnomAD3 exomes

AF:

0.00401

AC:

959

AN:

239166

Hom.:

AF XY:

0.00379

AC XY:

492

AN XY:

129780

show subpopulations

Gnomad AFR exome

AF:

0.000793

Gnomad AMR exome

AF:

0.00117

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0433

Gnomad SAS exome

AF:

0.00115

Gnomad FIN exome

AF:

0.0000486

Gnomad NFE exome

AF:

0.000883

Gnomad OTH exome

AF:

0.00348

GnomAD4 exome

AF:

0.00222

AC:

3235

AN:

1457482

Hom.:

Cov.:

AF XY:

0.00213

AC XY:

1541

AN XY:

724782

show subpopulations

Gnomad4 AFR exome

AF:

0.00129

Gnomad4 AMR exome

AF:

0.00148

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0499

Gnomad4 SAS exome

AF:

0.00126

Gnomad4 FIN exome

AF:

0.000134

Gnomad4 NFE exome

AF:

0.000787

Gnomad4 OTH exome

AF:

0.00247

GnomAD4 genome

AF:

0.00211

AC:

322

AN:

152322

Hom.:

Cov.:

AF XY:

0.00244

AC XY:

182

AN XY:

74484

show subpopulations

Gnomad4 AFR

AF:

0.000577

Gnomad4 AMR

AF:

0.00144

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.0387

Gnomad4 SAS

AF:

0.00248

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000794

Gnomad4 OTH

AF:

0.00426

Alfa

AF:

0.00239

Hom.:

Bravo

AF:

0.00265

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.000682

AC:

ESP6500EA

AF:

0.000698

AC:

ExAC

AF:

0.00370

AC:

448

Asia WGS

AF:

0.0130

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.069

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.39

CADD

Benign

1.2

DANN

Benign

0.91

DEOGEN2

Benign

0.18

T;.;.;.

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.025

LIST_S2

Benign

0.60

T;T;T;T

MetaRNN

Benign

0.0034

T;T;T;T

MetaSVM

Benign

-0.77

MutationAssessor

Benign

1.1

L;.;L;.

MutationTaster

Benign

1.0

N;N;N;N;N;N

PrimateAI

Benign

0.34

PROVEAN

Benign

-2.2

N;N;N;.

REVEL

Benign

0.12

Sift

Benign

0.14

T;T;T;.

Sift4G

Benign

0.17

T;T;T;T

Polyphen

0.0010

B;B;B;.

Vest4

0.058

MVP

0.87

MPC

0.38

ClinPred

0.0051

GERP RS

1.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.061

gMVP

0.34

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