rs2020902

Variant names:

• chr1-15507865-A-G
• rs2020902
• NM_001229.5:c.453+8T>C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_001229.5(CASP9):​c.453+8T>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 0.135 in 1,613,170 control chromosomes in the GnomAD database, including 15,484 homozygotes. 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 0.12 (1256 hom., cov: 33)
  • Exomes 𝑓: 0.14 (14228 hom.)
• Consequence: CASP9 NM_001229.5 splice_region, intron
• Scores: Splicing: ADA: 0.00004793
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: -0.435
• Publications: 42 publications found

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]

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 1-15507865-A-G is Benign according to our data. Variant chr1-15507865-A-G is described in ClinVar as Benign. ClinVar VariationId is 3060608.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.145 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CASP9	NM_001229.5	c.453+8T>C		splice_region_variant, intron_variant	Intron 3 of 8	ENST00000333868.10	NP_001220.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CASP9	ENST00000333868.10	c.453+8T>C		splice_region_variant, intron_variant	Intron 3 of 8	1	NM_001229.5	ENSP00000330237.5

Frequencies

GnomAD3 genomes AF: 0.123 AC: 18675 AN: 152136 Hom.: 1253 Cov.: 33

Gnomad AFR AF: 0.0920

Gnomad AMI AF: 0.123

Gnomad AMR AF: 0.108

Gnomad ASJ AF: 0.155

Gnomad EAS AF: 0.0389

Gnomad SAS AF: 0.0909

Gnomad FIN AF: 0.150

Gnomad MID AF: 0.158

Gnomad NFE AF: 0.147

Gnomad OTH AF: 0.125

GnomAD2 exomes AF: 0.122 AC: 30545 AN: 251294 AF XY: 0.125

Gnomad AFR exome AF: 0.0865

Gnomad AMR exome AF: 0.0869

Gnomad ASJ exome AF: 0.153

Gnomad EAS exome AF: 0.0358

Gnomad FIN exome AF: 0.150

Gnomad NFE exome AF: 0.145

Gnomad OTH exome AF: 0.135

GnomAD4 exome AF: 0.136 AC: 199170 AN: 1460916 Hom.: 14228 Cov.: 32 AF XY: 0.136 AC XY: 98941 AN XY: 726818

African (AFR) AF: 0.0872 AC: 2917 AN: 33466

American (AMR) AF: 0.0881 AC: 3937 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.155 AC: 4039 AN: 26116

East Asian (EAS) AF: 0.0544 AC: 2159 AN: 39696

South Asian (SAS) AF: 0.107 AC: 9200 AN: 86234

European-Finnish (FIN) AF: 0.152 AC: 8131 AN: 53386

Middle Eastern (MID) AF: 0.177 AC: 1018 AN: 5752

European-Non Finnish (NFE) AF: 0.144 AC: 159617 AN: 1111192

Other (OTH) AF: 0.135 AC: 8152 AN: 60362

GnomAD4 genome AF: 0.123 AC: 18680 AN: 152254 Hom.: 1256 Cov.: 33 AF XY: 0.121 AC XY: 8983 AN XY: 74454

African (AFR) AF: 0.0919 AC: 3817 AN: 41542

American (AMR) AF: 0.108 AC: 1652 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.155 AC: 539 AN: 3468

East Asian (EAS) AF: 0.0390 AC: 202 AN: 5180

South Asian (SAS) AF: 0.0905 AC: 437 AN: 4828

European-Finnish (FIN) AF: 0.150 AC: 1587 AN: 10610

Middle Eastern (MID) AF: 0.167 AC: 49 AN: 294

European-Non Finnish (NFE) AF: 0.147 AC: 10021 AN: 68012

Other (OTH) AF: 0.125 AC: 264 AN: 2112

Alfa AF: 0.138 Hom.: 3018

Bravo AF: 0.118

Asia WGS AF: 0.0720 AC: 250 AN: 3478

EpiCase AF: 0.145

EpiControl AF: 0.145

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

CASP9-related disorder Benign:1

Nov 25, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This 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	-0.83
CADD	Benign	0.77
DANN	Benign	0.60
PhyloP100		-0.43
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000048
dbscSNV1_RF	Benign	0.0
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs2020902; hg19: chr1-15834360;