Genetic Variant CASP9:p.Ser31Ser (chr1-15524108-G-A) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6BP7BA1

The NM_001229.5(CASP9):c.93C>T(p.Ser31Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.224 in 1,539,048 control chromosomes in the GnomAD database, including 41,438 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

Frequency

Genomes: 𝑓 0.28 ( 6670 hom., cov: 33)

Exomes 𝑓: 0.22 ( 34768 hom. )

Consequence

CASP9
NM_001229.5 synonymous

Scores

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: 0.149

Publications

38 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:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.68).

BP6

Variant 1-15524108-G-A is Benign according to our data. Variant chr1-15524108-G-A is described in ClinVar as Benign. ClinVar VariationId is 3059411.Status of the report is no_assertion_criteria_provided, 0 stars.

BP7

Synonymous conserved (PhyloP=0.149 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.421 is higher than 0.05.

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	UniProt
CASP9	NM_001229.5	MANE Select	c.93C>T	p.Ser31Ser	synonymous	Exon 1 of 9	NP_001220.2
CASP9	NM_001278054.2		c.93C>T	p.Ser31Ser	synonymous	Exon 1 of 5	NP_001264983.1	P55211-2
CASP9	NM_032996.3		c.-118+475C>T		intron	N/A	NP_127463.2	P55211-4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CASP9	ENST00000333868.10	TSL:1 MANE Select	c.93C>T	p.Ser31Ser	synonymous	Exon 1 of 9	ENSP00000330237.5	P55211-1
CASP9	ENST00000348549.9	TSL:1	c.93C>T	p.Ser31Ser	synonymous	Exon 1 of 5	ENSP00000255256.7	P55211-2
CASP9	ENST00000400777.7	TSL:1	n.84C>T		non_coding_transcript_exon	Exon 1 of 9	ENSP00000383588.3	H0Y3S8

Frequencies

GnomAD3 genomes

AF:

0.276

AC:

41977

AN:

151892

Hom.:

6643

Cov.:

show subpopulations

Gnomad AFR

AF:

0.425

Gnomad AMI

AF:

0.188

Gnomad AMR

AF:

0.192

Gnomad ASJ

AF:

0.254

Gnomad EAS

AF:

0.0650

Gnomad SAS

AF:

0.182

Gnomad FIN

AF:

0.281

Gnomad MID

AF:

0.231

Gnomad NFE

AF:

0.230

Gnomad OTH

AF:

0.269

GnomAD2 exomes

AF:

0.204

AC:

28052

AN:

137730

AF XY:

0.204

show subpopulations

Gnomad AFR exome

AF:

0.404

Gnomad AMR exome

AF:

0.135

Gnomad ASJ exome

AF:

0.261

Gnomad EAS exome

AF:

0.0641

Gnomad FIN exome

AF:

0.259

Gnomad NFE exome

AF:

0.214

Gnomad OTH exome

AF:

0.225

GnomAD4 exome

AF:

0.219

AC:

303378

AN:

1387044

Hom.:

34768

Cov.:

AF XY:

0.219

AC XY:

149764

AN XY:

685208

show subpopulations

African (AFR)

AF:

0.425

AC:

13074

AN:

30744

American (AMR)

AF:

0.143

AC:

5081

AN:

35600

Ashkenazi Jewish (ASJ)

AF:

0.262

AC:

6533

AN:

24898

East Asian (EAS)

AF:

0.0784

AC:

2791

AN:

35578

South Asian (SAS)

AF:

0.206

AC:

16281

AN:

78992

European-Finnish (FIN)

AF:

0.270

AC:

10851

AN:

40224

Middle Eastern (MID)

AF:

0.258

AC:

1046

AN:

4062

European-Non Finnish (NFE)

AF:

0.217

AC:

234659

AN:

1079272

Other (OTH)

AF:

0.226

AC:

13062

AN:

57674

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

Heterozygous variant carriers

11824

23648

35471

47295

59119

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

8086

16172

24258

32344

40430

<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:

0.277

AC:

42039

AN:

152004

Hom.:

6670

Cov.:

AF XY:

0.274

AC XY:

20337

AN XY:

74292

show subpopulations

African (AFR)

AF:

0.426

AC:

17639

AN:

41416

American (AMR)

AF:

0.192

AC:

2935

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.254

AC:

881

AN:

3468

East Asian (EAS)

AF:

0.0650

AC:

337

AN:

5182

South Asian (SAS)

AF:

0.180

AC:

870

AN:

4824

European-Finnish (FIN)

AF:

0.281

AC:

2968

AN:

10568

Middle Eastern (MID)

AF:

0.241

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.230

AC:

15608

AN:

67938

Other (OTH)

AF:

0.265

AC:

559

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

1446

2892

4338

5784

7230

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

412

824

1236

1648

2060

<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:

0.242

Hom.:

4958

Bravo

AF:

0.276

Asia WGS

AF:

0.161

AC:

556

AN:

3470

ClinVar

ClinVar submissions

Significance:Benign

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

CASP9-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.68

CADD

Benign

8.4

(source)

DANN

Benign

0.94

PhyloP100

0.15

PromoterAI

0.00040

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Mutation Taster

=100/0

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over