rs2042369

Variant names:

• chr1-15516749-G-A
• rs2042369
• NM_001229.5:c.418+1361C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001229.5(CASP9):​c.418+1361C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.273 in 152,082 control chromosomes in the GnomAD database, including 6,486 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 0.27 (6486 hom., cov: 33)
• Consequence: CASP9 NM_001229.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.650
• Publications: 11 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 (AFR) allele frequency at 95% confidence interval = 0.41 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001229.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CASP9	NM_001229.5	MANE Select	c.418+1361C>T		intron	N/A	NP_001220.2
	CASP9	NM_032996.3		c.169+1361C>T		intron	N/A	NP_127463.2	P55211-4
	CASP9	NM_001278054.2		c.418+1361C>T		intron	N/A	NP_001264983.1	P55211-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CASP9	ENST00000333868.10	TSL:1 MANE Select	c.418+1361C>T		intron	N/A	ENSP00000330237.5	P55211-1
	CASP9	ENST00000348549.9	TSL:1	c.418+1361C>T		intron	N/A	ENSP00000255256.7	P55211-2
	CASP9	ENST00000400777.7	TSL:1	n.409+1361C>T		intron	N/A	ENSP00000383588.3	H0Y3S8

Frequencies

GnomAD3 genomes AF: 0.273 AC: 41438 AN: 151964 Hom.: 6460 Cov.: 33

Gnomad AFR AF: 0.415

Gnomad AMI AF: 0.188

Gnomad AMR AF: 0.191

Gnomad ASJ AF: 0.254

Gnomad EAS AF: 0.0419

Gnomad SAS AF: 0.180

Gnomad FIN AF: 0.282

Gnomad MID AF: 0.231

Gnomad NFE AF: 0.230

Gnomad OTH AF: 0.268

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

GnomAD4 genome AF: 0.273 AC: 41500 AN: 152082 Hom.: 6486 Cov.: 33 AF XY: 0.270 AC XY: 20092 AN XY: 74360

African (AFR) AF: 0.415 AC: 17213 AN: 41454

American (AMR) AF: 0.190 AC: 2909 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.254 AC: 882 AN: 3472

East Asian (EAS) AF: 0.0420 AC: 218 AN: 5186

South Asian (SAS) AF: 0.178 AC: 861 AN: 4826

European-Finnish (FIN) AF: 0.282 AC: 2981 AN: 10562

Middle Eastern (MID) AF: 0.241 AC: 71 AN: 294

European-Non Finnish (NFE) AF: 0.230 AC: 15637 AN: 67984

Other (OTH) AF: 0.264 AC: 557 AN: 2108

Alfa AF: 0.249 Hom.: 901

Bravo AF: 0.271

Asia WGS AF: 0.154 AC: 535 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.62
DANN	Benign	0.45
PhyloP100		-0.65
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: rs2042369; hg19: chr1-15843244;