1-15493953-G-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001229.5(CASP9):c.1097C>A(p.Thr366Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00189 in 1,604,750 control chromosomes in the GnomAD database, including 48 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0086 ( 19 hom., cov: 32)

Exomes 𝑓: 0.0012 ( 29 hom. )

Consequence

CASP9
NM_001229.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 2.60

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=0.013510019).

BP6

Variant 1-15493953-G-T is Benign according to our data. Variant chr1-15493953-G-T is described in ClinVar as [Benign]. Clinvar id is 782360.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00862 (1312/152232) while in subpopulation AFR AF= 0.0285 (1185/41526). AF 95% confidence interval is 0.0272. There are 19 homozygotes in gnomad4. There are 625 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 1312 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CASP9	NM_001229.5 link	c.1097C>A	p.Thr366Asn	missense_variant	Exon 8 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.1097C>A	p.Thr366Asn	missense_variant	Exon 8 of 9	1	NM_001229.5	ENSP00000330237.5		P55211-1

Frequencies

GnomAD3 genomes

AF:

0.00862

AC:

1311

AN:

152114

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0286

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00510

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00104

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000441

Gnomad OTH

AF:

0.00718

GnomAD3 exomes

AF:

0.00235

AC:

553

AN:

235386

Hom.:

AF XY:

0.00192

AC XY:

244

AN XY:

127112

show subpopulations

Gnomad AFR exome

AF:

0.0269

Gnomad AMR exome

AF:

0.00108

Gnomad ASJ exome

AF:

0.000103

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00286

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000322

Gnomad OTH exome

AF:

0.00205

GnomAD4 exome

AF:

0.00118

AC:

1716

AN:

1452518

Hom.:

Cov.:

AF XY:

0.00112

AC XY:

810

AN XY:

721610

show subpopulations

Gnomad4 AFR exome

AF:

0.0282

Gnomad4 AMR exome

AF:

0.00151

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00272

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000301

Gnomad4 OTH exome

AF:

0.00225

GnomAD4 genome

AF:

0.00862

AC:

1312

AN:

152232

Hom.:

Cov.:

AF XY:

0.00840

AC XY:

625

AN XY:

74434

show subpopulations

Gnomad4 AFR

AF:

0.0285

Gnomad4 AMR

AF:

0.00510

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000830

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000441

Gnomad4 OTH

AF:

0.00710

Alfa

AF:

0.00124

Hom.:

Bravo

AF:

0.00988

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.0234

AC:

103

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.00269

AC:

326

Asia WGS

AF:

0.000866

AC:

AN:

3478

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

- -

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

CASP9-related disorder

Benign:1

May 28, 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

0.18

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.40

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.19

.;T;.;.

Eigen

Uncertain

0.42

Eigen_PC

Uncertain

0.42

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.85

T;D;D;D

MetaRNN

Benign

0.014

T;T;T;T

MetaSVM

Benign

-1.2

MutationAssessor

Uncertain

2.4

.;M;.;.

PrimateAI

Uncertain

0.55

PROVEAN

Uncertain

-2.9

D;D;D;D

REVEL

Benign

0.17

Sift

Benign

0.13

T;T;T;T

Sift4G

Benign

0.10

T;T;T;T

Polyphen

0.88

P;P;P;.

Vest4

0.59

MVP

0.78

MPC

0.38

ClinPred

0.058

GERP RS

5.7

Varity_R

0.60

gMVP

0.71

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