Genetic Variant NM_001229.5:c.721-5T>C (chr1-15504763-A-G) – ACMG Classification: Benign (-9 pts)

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_001229.5(CASP9):c.721-5T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000351 in 1,610,470 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (no stars).

Frequency

Genomes: 𝑓 0.0019 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00019 ( 0 hom. )

Consequence

CASP9
NM_001229.5 splice_region, intron

Scores

Splicing: ADA: 0.0005109

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: 1.95

Publications

3 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 -9 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.75).

BP6

Variant 1-15504763-A-G is Benign according to our data. Variant chr1-15504763-A-G is described in ClinVar as Benign. ClinVar VariationId is 3053478.Status of the report is no_assertion_criteria_provided, 0 stars.

BS2

High AC in GnomAd4 at 295 AD gene.

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	Effect	Exon Rank	Protein	UniProt
CASP9	NM_001229.5	MANE Select	c.721-5T>C	splice_region intron	N/A	NP_001220.2
CASP9	NM_032996.3		c.472-5T>C	splice_region intron	N/A	NP_127463.2	P55211-4
CASP9	NM_001278054.2		c.419-9311T>C	intron	N/A	NP_001264983.1	P55211-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
CASP9	ENST00000333868.10	TSL:1 MANE Select	c.721-5T>C	splice_region intron	N/A	ENSP00000330237.5	P55211-1
CASP9	ENST00000348549.9	TSL:1	c.419-9311T>C	intron	N/A	ENSP00000255256.7	P55211-2
CASP9	ENST00000400777.7	TSL:1	n.*314-5T>C	splice_region intron	N/A	ENSP00000383588.3	H0Y3S8

Frequencies

GnomAD3 genomes

AF:

0.00194

AC:

295

AN:

152246

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00690

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000392

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:

0.0000147

Gnomad OTH

AF:

0.000957

GnomAD2 exomes

AF:

0.000571

AC:

141

AN:

246838

AF XY:

0.000479

show subpopulations

Gnomad AFR exome

AF:

0.00824

Gnomad AMR exome

AF:

0.000179

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000333

GnomAD4 exome

AF:

0.000185

AC:

270

AN:

1458106

Hom.:

Cov.:

AF XY:

0.000160

AC XY:

116

AN XY:

725456

show subpopulations

African (AFR)

AF:

0.00665

AC:

221

AN:

33224

American (AMR)

AF:

0.000344

AC:

AN:

43644

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25912

East Asian (EAS)

AF:

0.00

AC:

AN:

39688

South Asian (SAS)

AF:

0.00

AC:

AN:

85744

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53336

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5738

European-Non Finnish (NFE)

AF:

0.00000270

AC:

AN:

1110620

Other (OTH)

AF:

0.000515

AC:

AN:

60200

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

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:

0.00194

AC:

295

AN:

152364

Hom.:

Cov.:

AF XY:

0.00189

AC XY:

141

AN XY:

74514

show subpopulations

African (AFR)

AF:

0.00688

AC:

286

AN:

41586

American (AMR)

AF:

0.000392

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68030

Other (OTH)

AF:

0.000947

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

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

Alfa

AF:

0.000897

Hom.:

Bravo

AF:

0.00224

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

CASP9-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.75

CADD

Benign

(source)

DANN

Benign

0.65

PhyloP100

1.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00051

dbscSNV1_RF

Benign

0.10

SpliceAI score (max)

0.20

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.20

Position offset: 12

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over