1-15506048-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BA1

The NM_001229.5(CASP9):c.662A>G(p.Gln221Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.537 in 1,612,996 control chromosomes in the GnomAD database, including 236,358 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

Frequency

Genomes: 𝑓 0.59 ( 26857 hom., cov: 32)

Exomes 𝑓: 0.53 ( 209501 hom. )

Consequence

CASP9
NM_001229.5 missense

Scores

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: -1.88

Publications

84 publications found

Variant links:

Genes affected

CASP9 (HGNC:1511): (caspase 9) This gene encodes a member of the cysteine-aspartic acid protease (caspase) family. Sequential activation of caspases plays a central role in the execution-phase of cell apoptosis. Caspases exist as inactive proenzymes which undergo proteolytic processing at conserved aspartic residues to produce two subunits, large and small, that dimerize to form the active enzyme. This protein can undergo autoproteolytic processing and activation by the apoptosome, a protein complex of cytochrome c and the apoptotic peptidase activating factor 1; this step is thought to be one of the earliest in the caspase activation cascade. This protein is thought to play a central role in apoptosis and to be a tumor suppressor. Alternative splicing results in multiple transcript variants. [provided by RefSeq, May 2013]

CASP9 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=1.5925274E-6).

BP6

Variant 1-15506048-T-C is Benign according to our data. Variant chr1-15506048-T-C is described in ClinVar as Benign. ClinVar VariationId is 3059116.Status of the report is no_assertion_criteria_provided, 0 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.699 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CASP9	NM_001229.5 link	c.662A>G	p.Gln221Arg	missense_variant	Exon 5 of 9	ENST00000333868.10	NP_001220.2	P55211-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CASP9	ENST00000333868.10 link	c.662A>G	p.Gln221Arg	missense_variant	Exon 5 of 9	1	NM_001229.5	ENSP00000330237.5		P55211-1

Frequencies

GnomAD3 genomes

AF:

0.587

AC:

89154

AN:

151946

Hom.:

26817

Cov.:

show subpopulations

Gnomad AFR

AF:

0.705

Gnomad AMI

AF:

0.514

Gnomad AMR

AF:

0.499

Gnomad ASJ

AF:

0.500

Gnomad EAS

AF:

0.647

Gnomad SAS

AF:

0.426

Gnomad FIN

AF:

0.652

Gnomad MID

AF:

0.510

Gnomad NFE

AF:

0.538

Gnomad OTH

AF:

0.557

GnomAD2 exomes

AF:

0.532

AC:

133595

AN:

251188

AF XY:

0.526

show subpopulations

Gnomad AFR exome

AF:

0.701

Gnomad AMR exome

AF:

0.410

Gnomad ASJ exome

AF:

0.492

Gnomad EAS exome

AF:

0.649

Gnomad FIN exome

AF:

0.645

Gnomad NFE exome

AF:

0.536

Gnomad OTH exome

AF:

0.522

GnomAD4 exome

AF:

0.532

AC:

776981

AN:

1460932

Hom.:

209501

Cov.:

AF XY:

0.529

AC XY:

384674

AN XY:

726838

show subpopulations

African (AFR)

AF:

0.704

AC:

23552

AN:

33464

American (AMR)

AF:

0.419

AC:

18732

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.499

AC:

13033

AN:

26136

East Asian (EAS)

AF:

0.644

AC:

25580

AN:

39690

South Asian (SAS)

AF:

0.432

AC:

37287

AN:

86240

European-Finnish (FIN)

AF:

0.638

AC:

34066

AN:

53388

Middle Eastern (MID)

AF:

0.510

AC:

2941

AN:

5766

European-Non Finnish (NFE)

AF:

0.530

AC:

589234

AN:

1111178

Other (OTH)

AF:

0.539

AC:

32556

AN:

60346

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

17378

34756

52133

69511

86889

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

16782

33564

50346

67128

83910

<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:

0.587

AC:

89242

AN:

152064

Hom.:

26857

Cov.:

AF XY:

0.587

AC XY:

43675

AN XY:

74342

show subpopulations

African (AFR)

AF:

0.706

AC:

29267

AN:

41472

American (AMR)

AF:

0.499

AC:

7615

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.500

AC:

1735

AN:

3472

East Asian (EAS)

AF:

0.647

AC:

3335

AN:

5158

South Asian (SAS)

AF:

0.425

AC:

2049

AN:

4826

European-Finnish (FIN)

AF:

0.652

AC:

6897

AN:

10576

Middle Eastern (MID)

AF:

0.524

AC:

153

AN:

292

European-Non Finnish (NFE)

AF:

0.538

AC:

36555

AN:

67976

Other (OTH)

AF:

0.554

AC:

1167

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1881

3762

5643

7524

9405

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

744

1488

2232

2976

3720

<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:

0.541

Hom.:

47168

Bravo

AF:

0.580

TwinsUK

AF:

0.523

AC:

1940

ALSPAC

AF:

0.528

AC:

2036

ESP6500AA

AF:

0.704

AC:

3101

ESP6500EA

AF:

0.528

AC:

4542

ExAC

AF:

0.536

AC:

65115

Asia WGS

AF:

0.554

AC:

1926

AN:

3478

EpiCase

AF:

0.520

EpiControl

AF:

0.516

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

CASP9-related disorder

Benign:1

Oct 18, 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

0.058

BayesDel_addAF

Benign

-0.70

BayesDel_noAF

Benign

-0.63

CADD

Benign

0.0010

(source)

DANN

Benign

0.16

DEOGEN2

Benign

0.045

.;T;.;T

Eigen

Benign

-2.3

Eigen_PC

Benign

-2.4

FATHMM_MKL

Benign

0.013

LIST_S2

Benign

0.047

T;T;T;T

MetaRNN

Benign

0.0000016

T;T;T;T

MetaSVM

Benign

-0.92

MutationAssessor

Benign

-0.50

.;N;.;.

PhyloP100

-1.9

PrimateAI

Benign

0.23

PROVEAN

Benign

0.71

N;N;N;N

REVEL

Benign

0.085

Sift

Benign

0.98

T;T;T;T

Sift4G

Benign

1.0

T;T;T;.

Polyphen

0.0

B;B;.;.

Vest4

0.017

MPC

0.13

ClinPred

0.014

GERP RS

-9.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.029

gMVP

0.24

Mutation Taster

=96/4

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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over