NM_001229.5:c.869-3248A>G

Variant names:

• chr1-15498700-T-C
• rs6685648
• NM_001229.5:c.869-3248A>G

Variant summary

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

The NM_001229.5(CASP9):​c.869-3248A>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
• Publications: 22 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=-0.7).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.565 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CASP9	NM_001229.5	MANE Select	c.869-3248A>G		intron	N/A	NP_001220.2
	CASP9	NM_032996.3		c.620-3248A>G		intron	N/A	NP_127463.2
	CASP9	NM_001278054.2		c.419-3248A>G		intron	N/A	NP_001264983.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CASP9	ENST00000333868.10	TSL:1 MANE Select	c.869-3248A>G		intron	N/A	ENSP00000330237.5
	CASP9	ENST00000348549.9	TSL:1	c.419-3248A>G		intron	N/A	ENSP00000255256.7
	CASP9	ENST00000400777.7	TSL:1	n.*462-3248A>G		intron	N/A	ENSP00000383588.3

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

African (AFR) AF: 0.264 AC: 10703 AN: 40474

American (AMR) AF: 0.302 AC: 4490 AN: 14882

Ashkenazi Jewish (ASJ) AF: 0.246 AC: 848 AN: 3446

East Asian (EAS) AF: 0.582 AC: 2924 AN: 5022

South Asian (SAS) AF: 0.247 AC: 1169 AN: 4736

European-Finnish (FIN) AF: 0.360 AC: 3428 AN: 9514

Middle Eastern (MID) AF: 0.287 AC: 81 AN: 282

European-Non Finnish (NFE) AF: 0.308 AC: 20814 AN: 67564

Other (OTH) AF: 0.284 AC: 588 AN: 2074

Alfa AF: 0.306 Hom.: 32159

Bravo AF: 0.300

Asia WGS AF: 0.393 AC: 1368 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	4.8
DANN	Benign	0.88
PhyloP100		0.21
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: rs6685648; hg19: chr1-15825195;