Genetic Variant CASP9:c.-118+13_-118+14insCGTGAGGTCAGTGCGGGGACGTGAGGTCAGTGCGGGGA (chr1-15524569-A-ATCCCCGCACTGACCTCACGTCCCCGCACTGACCTCACG) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_032996.3(CASP9):c.-118+13_-118+14insCGTGAGGTCAGTGCGGGGACGTGAGGTCAGTGCGGGGA variant causes a intron change involving the alteration of a non-conserved nucleotide. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 0)

Exomes 𝑓: 0.000018 ( 1 hom. )

Failed GnomAD Quality Control

Consequence

CASP9
NM_032996.3 intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.490

Publications

12 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032996.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CASP9	NM_032996.3		c.-118+13_-118+14insCGTGAGGTCAGTGCGGGGACGTGAGGTCAGTGCGGGGA		intron	N/A	NP_127463.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
CASP9	ENST00000375890.8	TSL:2	c.-118+13_-118+14insCGTGAGGTCAGTGCGGGGACGTGAGGTCAGTGCGGGGA	intron	N/A	ENSP00000365051.4
CASP9	ENST00000447522.5	TSL:3	c.-118+282_-118+283insCGTGAGGTCAGTGCGGGGACGTGAGGTCAGTGCGGGGA	intron	N/A	ENSP00000396540.1
CASP9	ENST00000469637.1	TSL:3	c.-239+1621_-239+1622insCGTGAGGTCAGTGCGGGGACGTGAGGTCAGTGCGGGGA	intron	N/A	ENSP00000480785.1

Frequencies

GnomAD3 genomes

AF:

0.0000386

AC:

AN:

51810

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000911

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000215

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000177

AC:

AN:

282546

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

138688

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

4720

American (AMR)

AF:

0.00

AC:

AN:

542

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2738

East Asian (EAS)

AF:

0.000859

AC:

AN:

1164

South Asian (SAS)

AF:

0.00

AC:

AN:

20690

European-Finnish (FIN)

AF:

0.000397

AC:

AN:

5036

Middle Eastern (MID)

AF:

0.00

AC:

AN:

712

European-Non Finnish (NFE)

AF:

0.00000423

AC:

AN:

236276

Other (OTH)

AF:

0.0000937

AC:

AN:

10668

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.308

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

AF:

0.0000386

AC:

AN:

51814

Hom.:

Cov.:

AF XY:

0.0000840

AC XY:

AN XY:

23810

show subpopulations

African (AFR)

AF:

0.0000908

AC:

AN:

11010

American (AMR)

AF:

0.000215

AC:

AN:

4646

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

1632

East Asian (EAS)

AF:

0.00

AC:

AN:

1646

South Asian (SAS)

AF:

0.00

AC:

AN:

1240

European-Finnish (FIN)

AF:

0.00

AC:

AN:

1888

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

28760

Other (OTH)

AF:

0.00

AC:

AN:

690

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.49

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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1-15524569-ATCCCCGCACTGACCTCACG-ATCCCCGCACTGACCTCACGTCCCCGCACTGACCTCACGTCCCCGCACTGACCTCACG

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