rs1052571

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -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. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). 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

Publications

64 publications found

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 was made for transcript

Our verdict: Benign. The variant received -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 VariationId 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

GnomAD2 exomes

AF:

0.503

AC:

68365

AN:

135782

AF XY:

0.499

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 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

African (AFR)

AF:

0.703

AC:

21625

AN:

30778

American (AMR)

AF:

0.426

AC:

15115

AN:

35458

Ashkenazi Jewish (ASJ)

AF:

0.494

AC:

12302

AN:

24900

East Asian (EAS)

AF:

0.640

AC:

22614

AN:

35340

South Asian (SAS)

AF:

0.431

AC:

33982

AN:

78866

European-Finnish (FIN)

AF:

0.626

AC:

25006

AN:

39952

Middle Eastern (MID)

AF:

0.481

AC:

1954

AN:

4064

European-Non Finnish (NFE)

AF:

0.529

AC:

570984

AN:

1078612

Other (OTH)

AF:

0.536

AC:

30877

AN:

57596

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

Heterozygous variant carriers

18157

36314

54471

72628

90785

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

16484

32968

49452

65936

82420

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.586

AC:

89003

AN:

151860

Hom.:

26741

Cov.:

AF XY:

0.587

AC XY:

43516

AN XY:

74194

show subpopulations

African (AFR)

AF:

0.705

AC:

29166

AN:

41382

American (AMR)

AF:

0.498

AC:

7618

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.493

AC:

1709

AN:

3468

East Asian (EAS)

AF:

0.646

AC:

3330

AN:

5154

South Asian (SAS)

AF:

0.424

AC:

2043

AN:

4816

European-Finnish (FIN)

AF:

0.651

AC:

6855

AN:

10538

Middle Eastern (MID)

AF:

0.524

AC:

154

AN:

294

European-Non Finnish (NFE)

AF:

0.538

AC:

36499

AN:

67904

Other (OTH)

AF:

0.551

AC:

1160

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

1799

3598

5396

7195

8994

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

740

1480

2220

2960

3700

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.545

Hom.:

56899

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

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) -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

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

(source)

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;.

PhyloP100

2.3

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

PromoterAI

-0.028

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.35

gMVP

0.11

Mutation Taster

=98/2

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over