rs4661636

chr1-15496566-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.869-1114G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.244 in 152,070 control chromosomes in the GnomAD database, including 5,739 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 0.24 (5739 hom., cov: 32)
• Consequence: CASP9 NM_001229.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.412

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

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.352 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CASP9	NM_001229.5	c.869-1114G>A		intron_variant		ENST00000333868.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CASP9	ENST00000333868.10	c.869-1114G>A		intron_variant		1	NM_001229.5	P1

Frequencies

GnomAD3 genomes AF: 0.244 AC: 37118 AN: 151952 Hom.: 5734 Cov.: 32

Gnomad AFR AF: 0.0607

Gnomad AMI AF: 0.152

Gnomad AMR AF: 0.341

Gnomad ASJ AF: 0.365

Gnomad EAS AF: 0.110

Gnomad SAS AF: 0.365

Gnomad FIN AF: 0.240

Gnomad MID AF: 0.314

Gnomad NFE AF: 0.330

Gnomad OTH AF: 0.283

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.244 AC: 37124 AN: 152070 Hom.: 5739 Cov.: 32 AF XY: 0.243 AC XY: 18038 AN XY: 74334

Gnomad4 AFR AF: 0.0605

Gnomad4 AMR AF: 0.342

Gnomad4 ASJ AF: 0.365

Gnomad4 EAS AF: 0.110

Gnomad4 SAS AF: 0.366

Gnomad4 FIN AF: 0.240

Gnomad4 NFE AF: 0.330

Gnomad4 OTH AF: 0.282

Alfa AF: 0.326 Hom.: 8007

Bravo AF: 0.244

Asia WGS AF: 0.221 AC: 770 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
Cadd	Benign	6.9
Dann	Benign	0.53

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

Other links and lift over

dbSNP: rs4661636; hg19: chr1-15823061; COSMIC: COSV61601147;