Genetic Variant CASP9:p.Asp369Asn (chr1-15493945-C-T) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2BP4_StrongBP6_Moderate

The NM_001229.5(CASP9):c.1105G>A(p.Asp369Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000275 in 1,452,668 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000028 ( 0 hom. )

Consequence

CASP9
NM_001229.5 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -2.99

Publications

0 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: Likely_benign. The variant received -4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.038060427).

BP6

Variant 1-15493945-C-T is Benign according to our data. Variant chr1-15493945-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 3485273.Status of the report is criteria_provided_single_submitter, 1 stars.

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.1105G>A	p.Asp369Asn	missense	Exon 8 of 9	NP_001220.2
CASP9	NM_032996.3		c.856G>A	p.Asp286Asn	missense	Exon 8 of 9	NP_127463.2	P55211-4
CASP9	NM_001278054.2		c.655G>A	p.Asp219Asn	missense	Exon 4 of 5	NP_001264983.1	P55211-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CASP9	ENST00000333868.10	TSL:1 MANE Select	c.1105G>A	p.Asp369Asn	missense	Exon 8 of 9	ENSP00000330237.5	P55211-1
CASP9	ENST00000348549.9	TSL:1	c.655G>A	p.Asp219Asn	missense	Exon 4 of 5	ENSP00000255256.7	P55211-2
CASP9	ENST00000400777.7	TSL:1	n.*698G>A		non_coding_transcript_exon	Exon 8 of 9	ENSP00000383588.3	H0Y3S8

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000275

AC:

AN:

1452668

Hom.:

Cov.:

AF XY:

0.00000277

AC XY:

AN XY:

721632

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33298

American (AMR)

AF:

0.00

AC:

AN:

43850

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25866

East Asian (EAS)

AF:

0.00

AC:

AN:

39434

South Asian (SAS)

AF:

0.0000118

AC:

AN:

84624

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52366

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.00000271

AC:

AN:

1107408

Other (OTH)

AF:

0.00

AC:

AN:

60062

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.412

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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

Cov.:

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.064

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.75

CADD

Benign

0.017

(source)

DANN

Benign

0.64

DEOGEN2

Benign

0.073

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.9

FATHMM_MKL

Benign

0.0048

LIST_S2

Benign

0.47

M_CAP

Benign

0.0022

MetaRNN

Benign

0.038

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.38

PhyloP100

-3.0

PrimateAI

Benign

0.22

PROVEAN

Benign

-0.73

REVEL

Benign

0.020

Sift

Benign

0.86

Sift4G

Benign

0.43

Polyphen

0.0020

Vest4

0.10

MutPred

0.50

Loss of phosphorylation at T366 (P = 0.298)

MVP

0.18

MPC

0.12

ClinPred

0.079

GERP RS

-11

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.11

gMVP

0.31

Mutation Taster

=92/8

polymorphism

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over