rs4661636

Variant names:

• chr1-15496566-C-T
• rs4661636
• NM_001229.5:c.869-1114G>A

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 17 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 -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 rank	MANE	Protein	UniProt
CASP9	NM_001229.5	c.869-1114G>A		intron_variant	Intron 6 of 8	ENST00000333868.10	NP_001220.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CASP9	ENST00000333868.10	c.869-1114G>A		intron_variant	Intron 6 of 8	1	NM_001229.5	ENSP00000330237.5

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

African (AFR) AF: 0.0605 AC: 2511 AN: 41506

American (AMR) AF: 0.342 AC: 5217 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.365 AC: 1267 AN: 3468

East Asian (EAS) AF: 0.110 AC: 568 AN: 5174

South Asian (SAS) AF: 0.366 AC: 1764 AN: 4820

European-Finnish (FIN) AF: 0.240 AC: 2530 AN: 10528

Middle Eastern (MID) AF: 0.298 AC: 87 AN: 292

European-Non Finnish (NFE) AF: 0.330 AC: 22446 AN: 67988

Other (OTH) AF: 0.282 AC: 596 AN: 2112

Alfa AF: 0.298 Hom.: 10201

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
PhyloP100		0.41
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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