dbSNP rs2975766: CAPN10:p.Ile666Val (chr2-240598657-A-G) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BA1

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. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in Lovd as Benign (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

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

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 -13 ACMG points.

BP4

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

BP6

Variant 2-240598657-A-G is Benign according to our data. Variant chr2-240598657-A-G is described in Lovd as [Benign].

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

GnomAD3 exomes

AF:

0.979

AC:

189056

AN:

193162

Hom.:

92544

AF XY:

0.978

AC XY:

100817

AN XY:

103112

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 SAS exome

AF:

0.987

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

Gnomad4 AFR exome

AF:

0.995

Gnomad4 AMR exome

AF:

0.981

Gnomad4 ASJ exome

AF:

0.955

Gnomad4 EAS exome

AF:

1.00

Gnomad4 SAS exome

AF:

0.985

Gnomad4 FIN exome

AF:

0.993

Gnomad4 NFE exome

AF:

0.968

Gnomad4 OTH exome

AF:

0.975

GnomAD4 genome

AF:

0.980

AC:

149260

AN:

152298

Hom.:

73164

Cov.:

AF XY:

0.981

AC XY:

73076

AN XY:

74470

show subpopulations

Gnomad4 AFR

AF:

0.994

Gnomad4 AMR

AF:

0.976

Gnomad4 ASJ

AF:

0.958

Gnomad4 EAS

AF:

1.00

Gnomad4 SAS

AF:

0.986

Gnomad4 FIN

AF:

0.993

Gnomad4 NFE

AF:

0.969

Gnomad4 OTH

AF:

0.974

Alfa

AF:

0.968

Hom.:

104714

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

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;.;.

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

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

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over