rs1286838324

Variant names:

• chr1-15495452-T-C
• rs1286838324
• NM_001229.5:c.869A>G

Your query was ambiguous. Multiple possible variants found:

• chr1-15495452-T-C
• chr1-15495452-T-G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001229.5(CASP9):​c.869A>G​(p.Glu290Gly) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000281 in 1,424,726 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 29)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: CASP9 NM_001229.5 missense, splice_region
• Scores: Splicing: ADA: 0.000003904
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.37
• Publications: 3 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16454402).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CASP9	NM_001229.5	MANE Select	c.869A>G	p.Glu290Gly	missense splice_region	Exon 7 of 9	NP_001220.2
	CASP9	NM_032996.3		c.620A>G	p.Glu207Gly	missense splice_region	Exon 7 of 9	NP_127463.2	P55211-4
	CASP9	NM_001278054.2		c.419A>G	p.Glu140Gly	missense splice_region	Exon 3 of 5	NP_001264983.1	P55211-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CASP9	ENST00000333868.10	TSL:1 MANE Select	c.869A>G	p.Glu290Gly	missense splice_region	Exon 7 of 9	ENSP00000330237.5	P55211-1
	CASP9	ENST00000348549.9	TSL:1	c.419A>G	p.Glu140Gly	missense splice_region	Exon 3 of 5	ENSP00000255256.7	P55211-2
	CASP9	ENST00000400777.7	TSL:1	n.*462A>G		splice_region non_coding_transcript_exon	Exon 7 of 9	ENSP00000383588.3	H0Y3S8

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome AF: 0.00000281 AC: 4 AN: 1424726 Hom.: 0 Cov.: 31 AF XY: 0.00000283 AC XY: 2 AN XY: 706378

African (AFR) AF: 0.0000939 AC: 3 AN: 31940

American (AMR) AF: 0.00 AC: 0 AN: 35840

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24730

East Asian (EAS) AF: 0.00 AC: 0 AN: 39036

South Asian (SAS) AF: 0.00 AC: 0 AN: 80772

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52324

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5652

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1095458

Other (OTH) AF: 0.0000170 AC: 1 AN: 58974

GnomAD4 genome Cov.: 29

Alfa AF: 0.0000329 Hom.: 0

Bravo AF: 0.0000340

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	17
DANN	Uncertain	1.0
DEOGEN2	Benign	0.17	T
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.41
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.69	T
M_CAP	Benign	0.0087	T
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.81	L
PhyloP100		1.4
PrimateAI	Benign	0.35	T
PROVEAN	Uncertain	-3.5	D
REVEL	Benign	0.11
Sift	Benign	0.28	T
Sift4G	Benign	0.24	T
Polyphen		0.0090	B
Vest4		0.21
MVP		0.41
MPC		0.15
ClinPred		0.69	D
GERP RS		2.5
Varity_R		0.37
gMVP		0.39
Mutation Taster		=78/22	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0000039
dbscSNV1_RF	Benign	0.016
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: rs1286838324; hg19: chr1-15821947;