Genetic Variant NM_001229.5:c.453+71C>T (chr1-15507802-G-A) – 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+71C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.537 in 1,485,308 control chromosomes in the GnomAD database, including 218,191 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 ( 26824 hom., cov: 32)

Exomes 𝑓: 0.53 ( 191367 hom. )

Consequence

CASP9
NM_001229.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.689

Publications

9 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=-0.84).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.699 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CASP9	NM_001229.5 link	c.453+71C>T		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+71C>T		intron_variant	Intron 3 of 8	1	NM_001229.5	ENSP00000330237.5		P55211-1

Frequencies

GnomAD3 genomes

AF:

0.586

AC:

89086

AN:

151912

Hom.:

26783

Cov.:

show subpopulations

Gnomad AFR

AF:

0.705

Gnomad AMI

AF:

0.514

Gnomad AMR

AF:

0.499

Gnomad ASJ

AF:

0.494

Gnomad EAS

AF:

0.647

Gnomad SAS

AF:

0.426

Gnomad FIN

AF:

0.650

Gnomad MID

AF:

0.509

Gnomad NFE

AF:

0.538

Gnomad OTH

AF:

0.555

GnomAD4 exome

AF:

0.532

AC:

709049

AN:

1333276

Hom.:

191367

Cov.:

AF XY:

0.529

AC XY:

354294

AN XY:

669712

show subpopulations

African (AFR)

AF:

0.703

AC:

21827

AN:

31040

American (AMR)

AF:

0.418

AC:

18453

AN:

44106

Ashkenazi Jewish (ASJ)

AF:

0.492

AC:

12304

AN:

25006

East Asian (EAS)

AF:

0.644

AC:

25167

AN:

39076

South Asian (SAS)

AF:

0.432

AC:

35967

AN:

83260

European-Finnish (FIN)

AF:

0.638

AC:

33754

AN:

52906

Middle Eastern (MID)

AF:

0.500

AC:

2418

AN:

4838

European-Non Finnish (NFE)

AF:

0.531

AC:

528977

AN:

997022

Other (OTH)

AF:

0.539

AC:

30182

AN:

56022

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

15644

31288

46933

62577

78221

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

14438

28876

43314

57752

72190

<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:

0.587

AC:

89176

AN:

152032

Hom.:

26824

Cov.:

AF XY:

0.587

AC XY:

43642

AN XY:

74324

show subpopulations

African (AFR)

AF:

0.706

AC:

29245

AN:

41450

American (AMR)

AF:

0.498

AC:

7615

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.494

AC:

1713

AN:

3470

East Asian (EAS)

AF:

0.647

AC:

3346

AN:

5170

South Asian (SAS)

AF:

0.424

AC:

2044

AN:

4818

European-Finnish (FIN)

AF:

0.650

AC:

6873

AN:

10566

Middle Eastern (MID)

AF:

0.524

AC:

154

AN:

294

European-Non Finnish (NFE)

AF:

0.538

AC:

36550

AN:

67958

Other (OTH)

AF:

0.552

AC:

1167

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1840

3681

5521

7362

9202

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:

0.567

Hom.:

3223

Bravo

AF:

0.581

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

-0.84

CADD

Benign

8.7

(source)

DANN

Benign

0.62

PhyloP100

0.69

Mutation Taster

=11/89

disease causing

(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