Genetic Variant NM_023083.4:c.1996A>G (chr2-240598657-A-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_023083.4(CAPN10):c.1996A>G(p.Ile666Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.973 in 1,579,140 control chromosomes in the GnomAD database, including 747,191 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.98 ( 73164 hom., cov: 33)

Exomes 𝑓: 0.97 ( 674027 hom. )

Consequence

CAPN10
NM_023083.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -2.09

Publications

35 publications found

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 Gene-Disease associations (from GenCC):

neurodevelopmental disorder
Inheritance: AR Classification: LIMITED Submitted by: G2P

CAPN10 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=8.433308E-7).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.986 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CAPN10	NM_023083.4 link	c.1996A>G	p.Ile666Val	missense_variant	Exon 12 of 12	ENST00000391984.7	NP_075571.2	Q9HC96-1
CAPN10	NM_023085.4 link	c.1531A>G	p.Ile511Val	missense_variant	Exon 10 of 10		NP_075573.3	Q9HC96-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CAPN10	ENST00000391984.7 link	c.1996A>G	p.Ile666Val	missense_variant	Exon 12 of 12	1	NM_023083.4	ENSP00000375844.2		Q9HC96-1

Frequencies

GnomAD3 genomes

AF:

0.980

AC:

149139

AN:

152180

Hom.:

73102

Cov.:

show subpopulations

Gnomad AFR

AF:

0.994

Gnomad AMI

AF:

1.00

Gnomad AMR

AF:

0.976

Gnomad ASJ

AF:

0.958

Gnomad EAS

AF:

1.00

Gnomad SAS

AF:

0.986

Gnomad FIN

AF:

0.993

Gnomad MID

AF:

0.968

Gnomad NFE

AF:

0.969

Gnomad OTH

AF:

0.974

GnomAD2 exomes

AF:

0.979

AC:

189056

AN:

193162

AF XY:

0.978

show subpopulations

Gnomad AFR exome

AF:

0.996

Gnomad AMR exome

AF:

0.981

Gnomad ASJ exome

AF:

0.956

Gnomad EAS exome

AF:

1.00

Gnomad FIN exome

AF:

0.995

Gnomad NFE exome

AF:

0.969

Gnomad OTH exome

AF:

0.975

GnomAD4 exome

AF:

0.972

AC:

1386816

AN:

1426842

Hom.:

674027

Cov.:

AF XY:

0.972

AC XY:

686170

AN XY:

706050

show subpopulations

African (AFR)

AF:

0.995

AC:

33040

AN:

33192

American (AMR)

AF:

0.981

AC:

37215

AN:

37944

Ashkenazi Jewish (ASJ)

AF:

0.955

AC:

24292

AN:

25432

East Asian (EAS)

AF:

1.00

AC:

38542

AN:

38546

South Asian (SAS)

AF:

0.985

AC:

80058

AN:

81300

European-Finnish (FIN)

AF:

0.993

AC:

50048

AN:

50424

Middle Eastern (MID)

AF:

0.965

AC:

5517

AN:

5720

European-Non Finnish (NFE)

AF:

0.968

AC:

1060425

AN:

1095098

Other (OTH)

AF:

0.975

AC:

57679

AN:

59186

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

1973

3945

5918

7890

9863

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

21458

42916

64374

85832

107290

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.980

AC:

149260

AN:

152298

Hom.:

73164

Cov.:

AF XY:

0.981

AC XY:

73076

AN XY:

74470

show subpopulations

African (AFR)

AF:

0.994

AC:

41332

AN:

41566

American (AMR)

AF:

0.976

AC:

14931

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.958

AC:

3326

AN:

3472

East Asian (EAS)

AF:

1.00

AC:

5166

AN:

5166

South Asian (SAS)

AF:

0.986

AC:

4763

AN:

4830

European-Finnish (FIN)

AF:

0.993

AC:

10557

AN:

10628

Middle Eastern (MID)

AF:

0.973

AC:

286

AN:

294

European-Non Finnish (NFE)

AF:

0.969

AC:

65925

AN:

68010

Other (OTH)

AF:

0.974

AC:

2062

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

149

298

446

595

744

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

916

1832

2748

3664

4580

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.969

Hom.:

147791

Bravo

AF:

0.979

TwinsUK

AF:

0.971

AC:

3600

ALSPAC

AF:

0.968

AC:

3732

ESP6500AA

AF:

0.995

AC:

4352

ESP6500EA

AF:

0.971

AC:

8312

ExAC

AF:

0.974

AC:

112490

Asia WGS

AF:

0.994

AC:

3456

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.42

CADD

Benign

0.057

(source)

DANN

Benign

0.24

DEOGEN2

Benign

0.095

T;.;.

Eigen

Benign

-1.8

Eigen_PC

Benign

-1.9

FATHMM_MKL

Benign

0.019

LIST_S2

Benign

0.071

T;T;T

MetaRNN

Benign

8.4e-7

T;T;T

MetaSVM

Benign

-0.94

MutationAssessor

Benign

-0.76

N;.;.

PhyloP100

-2.1

PrimateAI

Benign

0.35

PROVEAN

Benign

-0.25

N;N;N

REVEL

Benign

0.078

Sift

Benign

0.68

T;T;T

Sift4G

Benign

0.29

T;T;T

Polyphen

0.0

B;B;B

Vest4

0.019

MPC

0.29

ClinPred

0.00092

GERP RS

-6.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.3

Varity_R

0.014

gMVP

0.25

Mutation Taster

=99/1

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over