rs2020895

Positions:

• chr1-15494112-A-G
• chr1-15494112-A-T

Variant summary

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

The NM_001229.5(CASP9):​c.1049-111T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.541 in 1,337,928 control chromosomes in the GnomAD database, including 199,432 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 0.60 (27835 hom., cov: 31)
  • Exomes 𝑓: 0.53 (171597 hom.)
• Consequence: CASP9 NM_001229.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.70

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=-0.89).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.731 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CASP9	NM_001229.5	c.1049-111T>C		intron_variant		ENST00000333868.10	NP_001220.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CASP9	ENST00000333868.10	c.1049-111T>C		intron_variant		1	NM_001229.5	ENSP00000330237	P1

Frequencies

GnomAD3 genomes AF: 0.596 AC: 90486 AN: 151766 Hom.: 27789 Cov.: 31

Gnomad AFR AF: 0.737

Gnomad AMI AF: 0.512

Gnomad AMR AF: 0.504

Gnomad ASJ AF: 0.494

Gnomad EAS AF: 0.647

Gnomad SAS AF: 0.427

Gnomad FIN AF: 0.652

Gnomad MID AF: 0.509

Gnomad NFE AF: 0.538

Gnomad OTH AF: 0.566

GnomAD4 exome AF: 0.534 AC: 633545 AN: 1186042 Hom.: 171597 AF XY: 0.531 AC XY: 312147 AN XY: 587714

Gnomad4 AFR exome AF: 0.737

Gnomad4 AMR exome AF: 0.434

Gnomad4 ASJ exome AF: 0.494

Gnomad4 EAS exome AF: 0.645

Gnomad4 SAS exome AF: 0.433

Gnomad4 FIN exome AF: 0.630

Gnomad4 NFE exome AF: 0.532

Gnomad4 OTH exome AF: 0.542

GnomAD4 genome AF: 0.596 AC: 90580 AN: 151886 Hom.: 27835 Cov.: 31 AF XY: 0.597 AC XY: 44294 AN XY: 74224

Gnomad4 AFR AF: 0.738

Gnomad4 AMR AF: 0.504

Gnomad4 ASJ AF: 0.494

Gnomad4 EAS AF: 0.647

Gnomad4 SAS AF: 0.425

Gnomad4 FIN AF: 0.652

Gnomad4 NFE AF: 0.538

Gnomad4 OTH AF: 0.562

Alfa AF: 0.569 Hom.: 3124

Bravo AF: 0.591

Asia WGS AF: 0.560 AC: 1947 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.085
DANN	Benign	0.21

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2020895; hg19: chr1-15820607;