rs4646092

Positions:

• chr1-15495178-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001229.5(CASP9):​c.1048+95G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.23 in 1,158,462 control chromosomes in the GnomAD database, including 32,723 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.28 (6678 hom., cov: 29)
  • Exomes 𝑓: 0.22 (26045 hom.)
• Consequence: CASP9 NM_001229.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.296

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.422 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CASP9	NM_001229.5	c.1048+95G>A		intron_variant		ENST00000333868.10	NP_001220.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CASP9	ENST00000333868.10	c.1048+95G>A		intron_variant		1	NM_001229.5	ENSP00000330237.5

Frequencies

GnomAD3 genomes AF: 0.277 AC: 41952 AN: 151600 Hom.: 6649 Cov.: 29

Gnomad AFR AF: 0.426

Gnomad AMI AF: 0.184

Gnomad AMR AF: 0.192

Gnomad ASJ AF: 0.254

Gnomad EAS AF: 0.0639

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

GnomAD4 exome AF: 0.222 AC: 223984 AN: 1006744 Hom.: 26045 AF XY: 0.222 AC XY: 113302 AN XY: 510288

Gnomad4 AFR exome AF: 0.419

Gnomad4 AMR exome AF: 0.144

Gnomad4 ASJ exome AF: 0.261

Gnomad4 EAS exome AF: 0.0788

Gnomad4 SAS exome AF: 0.204

Gnomad4 FIN exome AF: 0.276

Gnomad4 NFE exome AF: 0.222

Gnomad4 OTH exome AF: 0.229

GnomAD4 genome AF: 0.277 AC: 42019 AN: 151718 Hom.: 6678 Cov.: 29 AF XY: 0.274 AC XY: 20327 AN XY: 74124

Gnomad4 AFR AF: 0.427

Gnomad4 AMR AF: 0.192

Gnomad4 ASJ AF: 0.254

Gnomad4 EAS AF: 0.0641

Gnomad4 SAS AF: 0.180

Gnomad4 FIN AF: 0.281

Gnomad4 NFE AF: 0.230

Gnomad4 OTH AF: 0.267

Alfa AF: 0.230 Hom.: 7074

Bravo AF: 0.276

Asia WGS AF: 0.163 AC: 563 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	13
DANN	Benign	0.78

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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

Other links and lift over

dbSNP: rs4646092; hg19: chr1-15821673;