rs1052571

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001229.5(CASP9):c.83C>T(p.Ala28Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.536 in 1,537,426 control chromosomes in the GnomAD database, including 223,949 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A28T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.59 ( 26741 hom., cov: 32)

Exomes 𝑓: 0.53 ( 197208 hom. )

Consequence

CASP9
NM_001229.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 2.25

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=5.70045E-6).

BP6

Variant 1-15524118-G-A is Benign according to our data. Variant chr1-15524118-G-A is described in ClinVar as [Benign]. Clinvar id is 1275295.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.698 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CASP9	NM_001229.5 link	c.83C>T	p.Ala28Val	missense_variant	Exon 1 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.83C>T	p.Ala28Val	missense_variant	Exon 1 of 9	1	NM_001229.5	ENSP00000330237.5		P55211-1

Frequencies

GnomAD3 genomes

AF:

0.586

AC:

88922

AN:

151748

Hom.:

26703

Cov.:

show subpopulations

Gnomad AFR

AF:

0.704

Gnomad AMI

AF:

0.514

Gnomad AMR

AF:

0.499

Gnomad ASJ

AF:

0.493

Gnomad EAS

AF:

0.646

Gnomad SAS

AF:

0.426

Gnomad FIN

AF:

0.651

Gnomad MID

AF:

0.509

Gnomad NFE

AF:

0.538

Gnomad OTH

AF:

0.555

GnomAD3 exomes

AF:

0.503

AC:

68365

AN:

135782

Hom.:

17840

AF XY:

0.499

AC XY:

36963

AN XY:

74062

show subpopulations

Gnomad AFR exome

AF:

0.685

Gnomad AMR exome

AF:

0.415

Gnomad ASJ exome

AF:

0.490

Gnomad EAS exome

AF:

0.631

Gnomad SAS exome

AF:

0.425

Gnomad FIN exome

AF:

0.617

Gnomad NFE exome

AF:

0.513

Gnomad OTH exome

AF:

0.500

GnomAD4 exome

AF:

0.530

AC:

734459

AN:

1385566

Hom.:

197208

Cov.:

AF XY:

0.527

AC XY:

360833

AN XY:

684316

show subpopulations

Gnomad4 AFR exome

AF:

0.703

Gnomad4 AMR exome

AF:

0.426

Gnomad4 ASJ exome

AF:

0.494

Gnomad4 EAS exome

AF:

0.640

Gnomad4 SAS exome

AF:

0.431

Gnomad4 FIN exome

AF:

0.626

Gnomad4 NFE exome

AF:

0.529

Gnomad4 OTH exome

AF:

0.536

GnomAD4 genome

AF:

0.586

AC:

89003

AN:

151860

Hom.:

26741

Cov.:

AF XY:

0.587

AC XY:

43516

AN XY:

74194

show subpopulations

Gnomad4 AFR

AF:

0.705

Gnomad4 AMR

AF:

0.498

Gnomad4 ASJ

AF:

0.493

Gnomad4 EAS

AF:

0.646

Gnomad4 SAS

AF:

0.424

Gnomad4 FIN

AF:

0.651

Gnomad4 NFE

AF:

0.538

Gnomad4 OTH

AF:

0.551

Alfa

AF:

0.535

Hom.:

37688

Bravo

AF:

0.580

ExAC

AF:

0.357

AC:

33850

Asia WGS

AF:

0.542

AC:

1874

AN:

3456

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 23, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 27984487) -

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

0.11

BayesDel_addAF

Benign

-0.63

BayesDel_noAF

Benign

-0.53

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.069

.;T;.;T

Eigen

Benign

-0.48

Eigen_PC

Benign

-0.47

FATHMM_MKL

Benign

0.078

LIST_S2

Benign

0.57

T;T;T;T

MetaRNN

Benign

0.0000057

T;T;T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

1.7

.;L;L;.

PrimateAI

Uncertain

0.54

PROVEAN

Benign

-1.1

N;N;N;N

REVEL

Benign

0.0050

Sift

Benign

0.53

T;T;T;T

Sift4G

Benign

0.13

T;T;T;.

Polyphen

0.029

B;B;P;.

Vest4

0.039

MPC

0.12

ClinPred

0.021

GERP RS

1.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.35

gMVP

0.11

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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