rs6685648

chr1-15498700-T-Cchr1-15498700-T-G

Variant summary

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

The NM_001229.5(CASP9):c.869-3248A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.304 in 148,896 control chromosomes in the GnomAD database, including 7,312 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 0.30 (7312 hom., cov: 27)
• Consequence: CASP9 NM_001229.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.207

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=-0.7).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.565 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CASP9	NM_001229.5	c.869-3248A>G		intron_variant		ENST00000333868.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CASP9	ENST00000333868.10	c.869-3248A>G		intron_variant		1	NM_001229.5	P1

Frequencies

GnomAD3 genomes AF: 0.305 AC: 45319 AN: 148808 Hom.: 7306 Cov.: 27

Gnomad AFR AF: 0.265

Gnomad AMI AF: 0.325

Gnomad AMR AF: 0.302

Gnomad ASJ AF: 0.246

Gnomad EAS AF: 0.582

Gnomad SAS AF: 0.246

Gnomad FIN AF: 0.360

Gnomad MID AF: 0.283

Gnomad NFE AF: 0.308

Gnomad OTH AF: 0.284

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

GnomAD4 genome AF: 0.304 AC: 45338 AN: 148896 Hom.: 7312 Cov.: 27 AF XY: 0.306 AC XY: 22173 AN XY: 72354

Gnomad4 AFR AF: 0.264

Gnomad4 AMR AF: 0.302

Gnomad4 ASJ AF: 0.246

Gnomad4 EAS AF: 0.582

Gnomad4 SAS AF: 0.247

Gnomad4 FIN AF: 0.360

Gnomad4 NFE AF: 0.308

Gnomad4 OTH AF: 0.284

Alfa AF: 0.304 Hom.: 14683

Bravo AF: 0.300

Asia WGS AF: 0.393 AC: 1368 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
Cadd	Benign	4.8
Dann	Benign	0.88

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: rs6685648; hg19: chr1-15825195;