NM_001229.5:c.869A>C

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001229.5(CASP9):​c.869A>C​(p.Glu290Ala) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000983 in 1,424,726 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E290G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 29)
  • Exomes 𝑓: 0.0000098 (0 hom.)
• Consequence: CASP9 NM_001229.5 missense, splice_region
• Scores: Splicing: ADA: 0.0007160
• Clinical Significance: Not reported in ClinVar
• 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.22598231).
• BS2: High AC in GnomAdExome4 at 14 AD gene.

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>C	p.Glu290Ala	missense splice_region	Exon 7 of 9	NP_001220.2
	CASP9	NM_032996.3		c.620A>C	p.Glu207Ala	missense splice_region	Exon 7 of 9	NP_127463.2	P55211-4
	CASP9	NM_001278054.2		c.419A>C	p.Glu140Ala	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>C	p.Glu290Ala	missense splice_region	Exon 7 of 9	ENSP00000330237.5	P55211-1
	CASP9	ENST00000348549.9	TSL:1	c.419A>C	p.Glu140Ala	missense splice_region	Exon 3 of 5	ENSP00000255256.7	P55211-2
	CASP9	ENST00000400777.7	TSL:1	n.*462A>C		splice_region non_coding_transcript_exon	Exon 7 of 9	ENSP00000383588.3	H0Y3S8

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD2 exomes AF: 0.00000981 AC: 2 AN: 203888 AF XY: 0.0000181

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000217

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000983 AC: 14 AN: 1424726 Hom.: 0 Cov.: 31 AF XY: 0.0000142 AC XY: 10 AN XY: 706378

African (AFR) AF: 0.00 AC: 0 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: 0.0000128 AC: 14 AN: 1095458

Other (OTH) AF: 0.00 AC: 0 AN: 58974

GnomAD4 genome Cov.: 29

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.17	T
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.25
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.0095	T
MetaRNN	Benign	0.23	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		1.4
PrimateAI	Benign	0.38	T
PROVEAN	Uncertain	-3.9	D
REVEL	Benign	0.10
Sift	Benign	0.055	T
Sift4G	Benign	0.18	T
Polyphen		0.20	B
Vest4		0.31
MutPred		0.54		Loss of ubiquitination at K292 (P = 0.0825)
MVP		0.51
MPC		0.26
ClinPred		0.38	T
GERP RS		2.5
Varity_R		0.37
gMVP		0.40
Mutation Taster		=76/24	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00072
dbscSNV1_RF	Benign	0.14
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;