rs4646092

Variant names:

• chr1-15495178-C-T
• rs4646092
• NM_001229.5:c.1048+95G>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.1048+95G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.23 in 1,158,462 control chromosomes in the GnomAD database, including 32,723 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 0.28 (6678 hom., cov: 29)
  • Exomes 𝑓: 0.22 (26045 hom.)
• Consequence: CASP9 NM_001229.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.296
• Publications: 15 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=-0.74).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.422 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CASP9	NM_001229.5	c.1048+95G>A		intron_variant	Intron 7 of 8	ENST00000333868.10	NP_001220.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CASP9	ENST00000333868.10	c.1048+95G>A		intron_variant	Intron 7 of 8	1	NM_001229.5	ENSP00000330237.5

Frequencies

GnomAD3 genomes AF: 0.277 AC: 41952 AN: 151600 Hom.: 6649 Cov.: 29

Gnomad AFR AF: 0.426

Gnomad AMI AF: 0.184

Gnomad AMR AF: 0.192

Gnomad ASJ AF: 0.254

Gnomad EAS AF: 0.0639

Gnomad SAS AF: 0.182

Gnomad FIN AF: 0.281

Gnomad MID AF: 0.231

Gnomad NFE AF: 0.230

Gnomad OTH AF: 0.269

GnomAD4 exome AF: 0.222 AC: 223984 AN: 1006744 Hom.: 26045 AF XY: 0.222 AC XY: 113302 AN XY: 510288

African (AFR) AF: 0.419 AC: 9320 AN: 22236

American (AMR) AF: 0.144 AC: 3719 AN: 25790

Ashkenazi Jewish (ASJ) AF: 0.261 AC: 5620 AN: 21520

East Asian (EAS) AF: 0.0788 AC: 2628 AN: 33352

South Asian (SAS) AF: 0.204 AC: 13302 AN: 65120

European-Finnish (FIN) AF: 0.276 AC: 13458 AN: 48796

Middle Eastern (MID) AF: 0.261 AC: 1099 AN: 4204

European-Non Finnish (NFE) AF: 0.222 AC: 164501 AN: 740634

Other (OTH) AF: 0.229 AC: 10337 AN: 45092

GnomAD4 genome AF: 0.277 AC: 42019 AN: 151718 Hom.: 6678 Cov.: 29 AF XY: 0.274 AC XY: 20327 AN XY: 74124

African (AFR) AF: 0.427 AC: 17634 AN: 41302

American (AMR) AF: 0.192 AC: 2923 AN: 15230

Ashkenazi Jewish (ASJ) AF: 0.254 AC: 882 AN: 3470

East Asian (EAS) AF: 0.0641 AC: 331 AN: 5164

South Asian (SAS) AF: 0.180 AC: 867 AN: 4816

European-Finnish (FIN) AF: 0.281 AC: 2961 AN: 10520

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

European-Non Finnish (NFE) AF: 0.230 AC: 15623 AN: 67914

Other (OTH) AF: 0.267 AC: 560 AN: 2100

Alfa AF: 0.243 Hom.: 13188

Bravo AF: 0.276

Asia WGS AF: 0.163 AC: 563 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	13
DANN	Benign	0.78
PhyloP100		0.30
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs4646092; hg19: chr1-15821673;