Genetic Variant CASP9:p.His237His (chr1-15505999-G-A) – ACMG Classification: Benign (-9 pts)

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_ModerateBP6_ModerateBP7BS2

The NM_001229.5(CASP9):c.711C>T(p.His237His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00227 in 1,613,814 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0017 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0023 ( 7 hom. )

Consequence

CASP9
NM_001229.5 synonymous

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:2

Conservation

PhyloP100: -1.06

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 -9 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.45).

BP6

Variant 1-15505999-G-A is Benign according to our data. Variant chr1-15505999-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 2638292.Status of the report is criteria_provided_single_submitter, 1 stars.

BP7

Synonymous conserved (PhyloP=-1.07 with no splicing effect.

BS2

High AC in GnomAd4 at 256 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CASP9	NM_001229.5 link	c.711C>T	p.His237His	synonymous_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.711C>T	p.His237His	synonymous_variant	Exon 5 of 9	1	NM_001229.5	ENSP00000330237.5		P55211-1

Frequencies

GnomAD3 genomes

AF:

0.00168

AC:

256

AN:

152232

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000482

Gnomad AMI

AF:

0.0285

Gnomad AMR

AF:

0.00105

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00275

Gnomad OTH

AF:

0.00287

GnomAD3 exomes

AF:

0.00147

AC:

370

AN:

251314

Hom.:

AF XY:

0.00133

AC XY:

181

AN XY:

135864

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.00127

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000980

Gnomad FIN exome

AF:

0.000323

Gnomad NFE exome

AF:

0.00267

Gnomad OTH exome

AF:

0.00179

GnomAD4 exome

AF:

0.00233

AC:

3406

AN:

1461464

Hom.:

Cov.:

AF XY:

0.00228

AC XY:

1661

AN XY:

727070

show subpopulations

Gnomad4 AFR exome

AF:

0.000358

Gnomad4 AMR exome

AF:

0.00123

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.000104

Gnomad4 FIN exome

AF:

0.000468

Gnomad4 NFE exome

AF:

0.00286

Gnomad4 OTH exome

AF:

0.00197

GnomAD4 genome

AF:

0.00168

AC:

256

AN:

152350

Hom.:

Cov.:

AF XY:

0.00132

AC XY:

AN XY:

74496

show subpopulations

Gnomad4 AFR

AF:

0.000481

Gnomad4 AMR

AF:

0.00105

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000941

Gnomad4 NFE

AF:

0.00275

Gnomad4 OTH

AF:

0.00284

Alfa

AF:

0.00210

Hom.:

Bravo

AF:

0.00211

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00267

EpiControl

AF:

0.00225

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

CASP9-related disorder

Benign:1

Mar 06, 2019

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided

Benign:1

Mar 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CASP9: BP4, BP7 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.45

CADD

Benign

0.091

DANN

Benign

0.73

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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