Variant 1-15506048-T-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBA1

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. 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 0.59 ( 26857 hom., cov: 32)

Exomes 𝑓: 0.53 ( 209501 hom. )

Consequence

CASP9
NM_001229.5 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -1.88

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 made for transcript

Verdict is Benign. Variant got -14 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 id is 3059116.Status of the report is criteria_provided_single_submitter, 1 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/exons	MANE	UniProt
CASP9	NM_001229.5 linkuse as main transcript	c.662A>G	p.Gln221Arg	missense_variant	5/9	ENST00000333868.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CASP9	ENST00000333868.10 linkuse as main transcript	c.662A>G	p.Gln221Arg	missense_variant	5/9	1	NM_001229.5	P1	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

GnomAD3 exomes

AF:

0.532

AC:

133595

AN:

251188

Hom.:

36699

AF XY:

0.526

AC XY:

71476

AN XY:

135778

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 SAS exome

AF:

0.431

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

Gnomad4 AFR exome

AF:

0.704

Gnomad4 AMR exome

AF:

0.419

Gnomad4 ASJ exome

AF:

0.499

Gnomad4 EAS exome

AF:

0.644

Gnomad4 SAS exome

AF:

0.432

Gnomad4 FIN exome

AF:

0.638

Gnomad4 NFE exome

AF:

0.530

Gnomad4 OTH exome

AF:

0.539

GnomAD4 genome

AF:

0.587

AC:

89242

AN:

152064

Hom.:

26857

Cov.:

AF XY:

0.587

AC XY:

43675

AN XY:

74342

show subpopulations

Gnomad4 AFR

AF:

0.706

Gnomad4 AMR

AF:

0.499

Gnomad4 ASJ

AF:

0.500

Gnomad4 EAS

AF:

0.647

Gnomad4 SAS

AF:

0.425

Gnomad4 FIN

AF:

0.652

Gnomad4 NFE

AF:

0.538

Gnomad4 OTH

AF:

0.554

Alfa

AF:

0.538

Hom.:

33419

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: criteria provided, single submitter

LINK: link

Submissions by phenotype

CASP9-related disorder

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 18, 2019

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

DANN

Benign

0.16

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

MutationTaster

Benign

1.0

P;P;P;P

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

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

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over