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GeneBe

rs4645983

chr1-15524108-G-A

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_StrongBP6_ModerateBP7BA1

The NM_001229.5(CASP9):c.93C>T(p.Ser31=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.224 in 1,539,048 control chromosomes in the GnomAD database, including 41,438 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.28 ( 6670 hom., cov: 33)
Exomes 𝑓: 0.22 ( 34768 hom. )

Consequence

CASP9
NM_001229.5 synonymous

Scores

2

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.149
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -15 ACMG points.

BP4
?
    BP4 - Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)
Computational evidence support a benign effect (BayesDel_noAF=-0.68).
BP6
?
    BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 1-15524108-G-A is Benign according to our data. Variant chr1-15524108-G-A is described in ClinVar as [Benign]. Clinvar id is 3059411.Status of the report is criteria_provided_single_submitter, 1 stars.
BP7
?
    BP7 - A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved
Synonymous conserved (PhyloP=0.149 with no splicing effect.
BA1
?
    BA1 - Allele frequency is >5% in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium
GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.421 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
CASP9NM_001229.5 linkuse as main transcriptc.93C>T p.Ser31= synonymous_variant 1/9 ENST00000333868.10

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
CASP9ENST00000333868.10 linkuse as main transcriptc.93C>T p.Ser31= synonymous_variant 1/91 NM_001229.5 P1P55211-1

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.276
AC:
41977
AN:
151892
Hom.:
6643
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.425
Gnomad AMI
AF:
0.188
Gnomad AMR
AF:
0.192
Gnomad ASJ
AF:
0.254
Gnomad EAS
AF:
0.0650
Gnomad SAS
AF:
0.182
Gnomad FIN
AF:
0.281
Gnomad MID
AF:
0.231
Gnomad NFE
AF:
0.230
Gnomad OTH
AF:
0.269
GnomAD3 exomes
AF:
0.204
AC:
28052
AN:
137730
Hom.:
3247
AF XY:
0.204
AC XY:
15329
AN XY:
75068
show subpopulations
Gnomad AFR exome
AF:
0.404
Gnomad AMR exome
AF:
0.135
Gnomad ASJ exome
AF:
0.261
Gnomad EAS exome
AF:
0.0641
Gnomad SAS exome
AF:
0.210
Gnomad FIN exome
AF:
0.259
Gnomad NFE exome
AF:
0.214
Gnomad OTH exome
AF:
0.225
GnomAD4 exome
AF:
0.219
AC:
303378
AN:
1387044
Hom.:
34768
Cov.:
42
AF XY:
0.219
AC XY:
149764
AN XY:
685208
show subpopulations
Gnomad4 AFR exome
AF:
0.425
Gnomad4 AMR exome
AF:
0.143
Gnomad4 ASJ exome
AF:
0.262
Gnomad4 EAS exome
AF:
0.0784
Gnomad4 SAS exome
AF:
0.206
Gnomad4 FIN exome
AF:
0.270
Gnomad4 NFE exome
AF:
0.217
Gnomad4 OTH exome
AF:
0.226
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.277
AC:
42039
AN:
152004
Hom.:
6670
Cov.:
33
AF XY:
0.274
AC XY:
20337
AN XY:
74292
show subpopulations
Gnomad4 AFR
AF:
0.426
Gnomad4 AMR
AF:
0.192
Gnomad4 ASJ
AF:
0.254
Gnomad4 EAS
AF:
0.0650
Gnomad4 SAS
AF:
0.180
Gnomad4 FIN
AF:
0.281
Gnomad4 NFE
AF:
0.230
Gnomad4 OTH
AF:
0.265
Alfa
AF:
0.233
Hom.:
3529
Bravo
AF:
0.276
Asia WGS
AF:
0.161
AC:
556
AN:
3470

ClinVar

Significance: Benign
Submissions summary: Benign:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

CASP9-related disorder Benign:1
Benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesNov 08, 2019This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.68
Cadd
Benign
8.4
Dann
Benign
0.94
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.0

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs4645983; hg19: chr1-15850603; COSMIC: COSV61600793; COSMIC: COSV61600793; API