dbSNP rs2020895: CASP9:c.1049-111T>C (chr1-15494112-A-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001229.5(CASP9):c.1049-111T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.541 in 1,337,928 control chromosomes in the GnomAD database, including 199,432 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.60 ( 27835 hom., cov: 31)

Exomes 𝑓: 0.53 ( 171597 hom. )

Consequence

CASP9
NM_001229.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.70

Publications

6 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 -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.89).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.731 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CASP9	NM_001229.5 link	c.1049-111T>C		intron_variant	Intron 7 of 8	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.1049-111T>C		intron_variant	Intron 7 of 8	1	NM_001229.5	ENSP00000330237.5		P55211-1

Frequencies

GnomAD3 genomes

AF:

0.596

AC:

90486

AN:

151766

Hom.:

27789

Cov.:

show subpopulations

Gnomad AFR

AF:

0.737

Gnomad AMI

AF:

0.512

Gnomad AMR

AF:

0.504

Gnomad ASJ

AF:

0.494

Gnomad EAS

AF:

0.647

Gnomad SAS

AF:

0.427

Gnomad FIN

AF:

0.652

Gnomad MID

AF:

0.509

Gnomad NFE

AF:

0.538

Gnomad OTH

AF:

0.566

GnomAD4 exome

AF:

0.534

AC:

633545

AN:

1186042

Hom.:

171597

AF XY:

0.531

AC XY:

312147

AN XY:

587714

show subpopulations

African (AFR)

AF:

0.737

AC:

20558

AN:

27898

American (AMR)

AF:

0.434

AC:

14271

AN:

32894

Ashkenazi Jewish (ASJ)

AF:

0.494

AC:

10548

AN:

21364

East Asian (EAS)

AF:

0.645

AC:

22322

AN:

34628

South Asian (SAS)

AF:

0.433

AC:

29979

AN:

69306

European-Finnish (FIN)

AF:

0.630

AC:

20635

AN:

32742

Middle Eastern (MID)

AF:

0.497

AC:

1904

AN:

3828

European-Non Finnish (NFE)

AF:

0.532

AC:

485724

AN:

912412

Other (OTH)

AF:

0.542

AC:

27604

AN:

50970

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

14631

29262

43893

58524

73155

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

13514

27028

40542

54056

67570

<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:

0.596

AC:

90580

AN:

151886

Hom.:

27835

Cov.:

AF XY:

0.597

AC XY:

44294

AN XY:

74224

show subpopulations

African (AFR)

AF:

0.738

AC:

30565

AN:

41426

American (AMR)

AF:

0.504

AC:

7696

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.494

AC:

1713

AN:

3470

East Asian (EAS)

AF:

0.647

AC:

3331

AN:

5150

South Asian (SAS)

AF:

0.425

AC:

2044

AN:

4808

European-Finnish (FIN)

AF:

0.652

AC:

6874

AN:

10544

Middle Eastern (MID)

AF:

0.524

AC:

154

AN:

294

European-Non Finnish (NFE)

AF:

0.538

AC:

36557

AN:

67904

Other (OTH)

AF:

0.562

AC:

1183

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

1790

3580

5371

7161

8951

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

742

1484

2226

2968

3710

<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:

0.574

Hom.:

3305

Bravo

AF:

0.591

Asia WGS

AF:

0.560

AC:

1947

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.89

CADD

Benign

0.085

(source)

DANN

Benign

0.21

PhyloP100

-1.7

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over