1-15494112-A-G

Variant names:

• chr1-15494112-A-G
• rs2020895
• NM_001229.5:c.1049-111T>C

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 6 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=-0.89).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.731 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.1049-111T>C		intron	N/A	NP_001220.2
	CASP9	NM_032996.3		c.800-111T>C		intron	N/A	NP_127463.2
	CASP9	NM_001278054.2		c.599-111T>C		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.1049-111T>C		intron	N/A	ENSP00000330237.5
	CASP9	ENST00000348549.9	TSL:1	c.599-111T>C		intron	N/A	ENSP00000255256.7
	CASP9	ENST00000400777.7	TSL:1	n.*642-111T>C		intron	N/A	ENSP00000383588.3

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

African (AFR) AF: 0.737 AC: 20558 AN: 27898

American (AMR) AF: 0.434 AC: 14271 AN: 32894

Ashkenazi Jewish (ASJ) AF: 0.494 AC: 10548 AN: 21364

East Asian (EAS) AF: 0.645 AC: 22322 AN: 34628

South Asian (SAS) AF: 0.433 AC: 29979 AN: 69306

European-Finnish (FIN) AF: 0.630 AC: 20635 AN: 32742

Middle Eastern (MID) AF: 0.497 AC: 1904 AN: 3828

European-Non Finnish (NFE) AF: 0.532 AC: 485724 AN: 912412

Other (OTH) AF: 0.542 AC: 27604 AN: 50970

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

African (AFR) AF: 0.738 AC: 30565 AN: 41426

American (AMR) AF: 0.504 AC: 7696 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.494 AC: 1713 AN: 3470

East Asian (EAS) AF: 0.647 AC: 3331 AN: 5150

South Asian (SAS) AF: 0.425 AC: 2044 AN: 4808

European-Finnish (FIN) AF: 0.652 AC: 6874 AN: 10544

Middle Eastern (MID) AF: 0.524 AC: 154 AN: 294

European-Non Finnish (NFE) AF: 0.538 AC: 36557 AN: 67904

Other (OTH) AF: 0.562 AC: 1183 AN: 2106

Alfa AF: 0.574 Hom.: 3305

Bravo AF: 0.591

Asia WGS AF: 0.560 AC: 1947 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.085
DANN	Benign	0.21
PhyloP100		-1.7
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2020895; hg19: chr1-15820607;