Variant 1-15507011-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_001229.5(CASP9):c.518G>A(p.Arg173His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0122 in 1,614,178 control chromosomes in the GnomAD database, including 174 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 the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.011 ( 15 hom., cov: 32)

Exomes 𝑓: 0.012 ( 159 hom. )

Consequence

CASP9
NM_001229.5 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:2

Conservation

PhyloP100: -1.94

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0027354658).

BP6

Variant 1-15507011-C-T is Benign according to our data. Variant chr1-15507011-C-T is described in ClinVar as [Benign]. Clinvar id is 3041435.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High AC in GnomAd4 at 1643 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CASP9	NM_001229.5 link	c.518G>A	p.Arg173His	missense_variant	4/9	ENST00000333868.10	NP_001220.2	P55211-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CASP9	ENST00000333868.10 link	c.518G>A	p.Arg173His	missense_variant	4/9	1	NM_001229.5	ENSP00000330237.5		P55211-1

Frequencies

GnomAD3 genomes

AF:

0.0108

AC:

1644

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00246

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00976

Gnomad ASJ

AF:

0.00835

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00166

Gnomad FIN

AF:

0.0347

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0144

Gnomad OTH

AF:

0.00431

GnomAD3 exomes

AF:

0.0108

AC:

2721

AN:

251400

Hom.:

AF XY:

0.0110

AC XY:

1493

AN XY:

135880

show subpopulations

Gnomad AFR exome

AF:

0.00258

Gnomad AMR exome

AF:

0.00625

Gnomad ASJ exome

AF:

0.00397

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00134

Gnomad FIN exome

AF:

0.0370

Gnomad NFE exome

AF:

0.0133

Gnomad OTH exome

AF:

0.0101

GnomAD4 exome

AF:

0.0123

AC:

18031

AN:

1461858

Hom.:

159

Cov.:

AF XY:

0.0121

AC XY:

8835

AN XY:

727234

show subpopulations

Gnomad4 AFR exome

AF:

0.00215

Gnomad4 AMR exome

AF:

0.00635

Gnomad4 ASJ exome

AF:

0.00547

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00133

Gnomad4 FIN exome

AF:

0.0345

Gnomad4 NFE exome

AF:

0.0135

Gnomad4 OTH exome

AF:

0.0101

GnomAD4 genome

AF:

0.0108

AC:

1643

AN:

152320

Hom.:

Cov.:

AF XY:

0.0116

AC XY:

865

AN XY:

74470

show subpopulations

Gnomad4 AFR

AF:

0.00245

Gnomad4 AMR

AF:

0.00974

Gnomad4 ASJ

AF:

0.00835

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00145

Gnomad4 FIN

AF:

0.0347

Gnomad4 NFE

AF:

0.0144

Gnomad4 OTH

AF:

0.00427

Alfa

AF:

0.0114

Hom.:

Bravo

AF:

0.00810

TwinsUK

AF:

0.00998

AC:

ALSPAC

AF:

0.0145

AC:

ESP6500AA

AF:

0.00363

AC:

ESP6500EA

AF:

0.0131

AC:

113

ExAC

AF:

0.0105

AC:

1273

Asia WGS

AF:

0.00173

AC:

AN:

3476

EpiCase

AF:

0.0121

EpiControl

AF:

0.0117

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

CASP9-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 05, 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). -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Aug 01, 2024

CASP9: BP4, BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.069

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.58

CADD

Benign

0.0050

DANN

Benign

0.91

DEOGEN2

Benign

0.070

.;T;.;T;T

Eigen

Benign

-2.1

Eigen_PC

Benign

-2.2

FATHMM_MKL

Benign

0.026

LIST_S2

Benign

0.19

T;T;T;T;T

MetaRNN

Benign

0.0027

T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.3

.;L;.;.;.

PrimateAI

Benign

0.21

PROVEAN

Benign

-1.1

N;N;N;N;N

REVEL

Benign

0.072

Sift

Benign

0.25

T;T;T;T;T

Sift4G

Benign

0.14

T;T;T;.;.

Polyphen

0.012

B;B;.;.;.

Vest4

0.10

MPC

0.16

ClinPred

0.017

GERP RS

-12

Varity_R

0.078

gMVP

0.43

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

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