Genetic Variant NM_001229.5:c.453+208A>G (chr1-15507665-T-C) – 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.453+208A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.551 in 576,072 control chromosomes in the GnomAD database, including 89,808 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 0.59 ( 26938 hom., cov: 31)

Exomes 𝑓: 0.54 ( 62870 hom. )

Consequence

CASP9
NM_001229.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.651

Publications

5 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=-0.93).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.703 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CASP9	NM_001229.5 link	c.453+208A>G		intron_variant	Intron 3 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.453+208A>G		intron_variant	Intron 3 of 8	1	NM_001229.5	ENSP00000330237.5		P55211-1

Frequencies

GnomAD3 genomes

AF:

0.587

AC:

89230

AN:

151884

Hom.:

26899

Cov.:

show subpopulations

Gnomad AFR

AF:

0.709

Gnomad AMI

AF:

0.512

Gnomad AMR

AF:

0.498

Gnomad ASJ

AF:

0.494

Gnomad EAS

AF:

0.647

Gnomad SAS

AF:

0.426

Gnomad FIN

AF:

0.651

Gnomad MID

AF:

0.509

Gnomad NFE

AF:

0.538

Gnomad OTH

AF:

0.556

GnomAD4 exome

AF:

0.538

AC:

228141

AN:

424072

Hom.:

62870

AF XY:

0.532

AC XY:

118804

AN XY:

223510

show subpopulations

African (AFR)

AF:

0.705

AC:

8313

AN:

11784

American (AMR)

AF:

0.446

AC:

7507

AN:

16850

Ashkenazi Jewish (ASJ)

AF:

0.490

AC:

6273

AN:

12790

East Asian (EAS)

AF:

0.642

AC:

18914

AN:

29482

South Asian (SAS)

AF:

0.427

AC:

17889

AN:

41866

European-Finnish (FIN)

AF:

0.627

AC:

18905

AN:

30168

Middle Eastern (MID)

AF:

0.495

AC:

912

AN:

1842

European-Non Finnish (NFE)

AF:

0.534

AC:

136042

AN:

254714

Other (OTH)

AF:

0.545

AC:

13386

AN:

24576

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

4633

9266

13899

18532

23165

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

704

1408

2112

2816

3520

<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:

0.588

AC:

89317

AN:

152000

Hom.:

26938

Cov.:

AF XY:

0.588

AC XY:

43698

AN XY:

74320

show subpopulations

African (AFR)

AF:

0.709

AC:

29410

AN:

41464

American (AMR)

AF:

0.498

AC:

7612

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.494

AC:

1712

AN:

3464

East Asian (EAS)

AF:

0.647

AC:

3335

AN:

5152

South Asian (SAS)

AF:

0.424

AC:

2045

AN:

4820

European-Finnish (FIN)

AF:

0.651

AC:

6878

AN:

10570

Middle Eastern (MID)

AF:

0.524

AC:

154

AN:

294

European-Non Finnish (NFE)

AF:

0.538

AC:

36538

AN:

67938

Other (OTH)

AF:

0.553

AC:

1168

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1854

3709

5563

7418

9272

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:

0.468

Hom.:

1528

Bravo

AF:

0.582

Asia WGS

AF:

0.553

AC:

1924

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.93

CADD

Benign

4.7

(source)

DANN

Benign

0.28

PhyloP100

-0.65

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over