NM_001229.5:c.518G>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

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

Publications

19 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 -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 VariationId is 3041435.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High AC in GnomAd4 at 1643 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001229.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CASP9	NM_001229.5	MANE Select	c.518G>A	p.Arg173His	missense	Exon 4 of 9	NP_001220.2
CASP9	NM_032996.3		c.269G>A	p.Arg90His	missense	Exon 4 of 9	NP_127463.2
CASP9	NR_102732.2		n.591G>A		non_coding_transcript_exon	Exon 4 of 9

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CASP9	ENST00000333868.10	TSL:1 MANE Select	c.518G>A	p.Arg173His	missense	Exon 4 of 9	ENSP00000330237.5
CASP9	ENST00000400777.7	TSL:1	n.*111G>A		non_coding_transcript_exon	Exon 4 of 9	ENSP00000383588.3
CASP9	ENST00000474305.2	TSL:1	n.*90G>A		non_coding_transcript_exon	Exon 4 of 9	ENSP00000449216.1

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

GnomAD2 exomes

AF:

0.0108

AC:

2721

AN:

251400

AF XY:

0.0110

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 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

African (AFR)

AF:

0.00215

AC:

AN:

33480

American (AMR)

AF:

0.00635

AC:

284

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00547

AC:

143

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00133

AC:

115

AN:

86254

European-Finnish (FIN)

AF:

0.0345

AC:

1843

AN:

53418

Middle Eastern (MID)

AF:

0.00139

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0135

AC:

14957

AN:

1111988

Other (OTH)

AF:

0.0101

AC:

609

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

895

1790

2685

3580

4475

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

540

1080

1620

2160

2700

<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:

0.0108

AC:

1643

AN:

152320

Hom.:

Cov.:

AF XY:

0.0116

AC XY:

865

AN XY:

74470

show subpopulations

African (AFR)

AF:

0.00245

AC:

102

AN:

41592

American (AMR)

AF:

0.00974

AC:

149

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00835

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00145

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.0347

AC:

368

AN:

10608

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0144

AC:

977

AN:

68030

Other (OTH)

AF:

0.00427

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

170

256

341

426

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.0114

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

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

CASP9-related disorder (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.069

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.58

CADD

Benign

0.0050

(source)

DANN

Benign

0.91

DEOGEN2

Benign

0.070

Eigen

Benign

-2.1

Eigen_PC

Benign

-2.2

FATHMM_MKL

Benign

0.026

LIST_S2

Benign

0.19

MetaRNN

Benign

0.0027

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.3

PhyloP100

-1.9

PrimateAI

Benign

0.21

PROVEAN

Benign

-1.1

REVEL

Benign

0.072

Sift

Benign

0.25

Sift4G

Benign

0.14

Polyphen

0.012

Vest4

0.10

MPC

0.16

ClinPred

0.017

GERP RS

-12

PromoterAI

0.037

Neutral

(source)

Varity_R

0.078

gMVP

0.43

Mutation Taster

=99/1

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over