rs1132312

Variant names:

• chr1-15518120-A-C
• rs1132312
• NM_001229.5:c.408T>G

Your query was ambiguous. Multiple possible variants found:

• chr1-15518120-A-C
• chr1-15518120-A-G
• chr1-15518120-A-T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001229.5(CASP9):​c.408T>G​(p.Phe136Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. F136F) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CASP9 NM_001229.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.325
• Publications: 21 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 -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.055832505).

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.408T>G	p.Phe136Leu	missense	Exon 2 of 9	NP_001220.2
	CASP9	NM_032996.3		c.159T>G	p.Phe53Leu	missense	Exon 2 of 9	NP_127463.2
	CASP9	NM_001278054.2		c.408T>G	p.Phe136Leu	missense	Exon 2 of 5	NP_001264983.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CASP9	ENST00000333868.10	TSL:1 MANE Select	c.408T>G	p.Phe136Leu	missense	Exon 2 of 9	ENSP00000330237.5
	CASP9	ENST00000348549.9	TSL:1	c.408T>G	p.Phe136Leu	missense	Exon 2 of 5	ENSP00000255256.7
	CASP9	ENST00000400777.7	TSL:1	n.399T>G		non_coding_transcript_exon	Exon 2 of 9	ENSP00000383588.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 54

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	0.25
DANN	Benign	0.21
DEOGEN2	Benign	0.060	T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.041	N
LIST_S2	Benign	0.47	T
M_CAP	Benign	0.0038	T
MetaRNN	Benign	0.056	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.94	L
PhyloP100		-0.33
PrimateAI	Benign	0.38	T
PROVEAN	Benign	0.020	N
REVEL	Benign	0.017
Sift	Benign	0.72	T
Sift4G	Benign	0.58	T
Polyphen		0.0	B
Vest4		0.044
MutPred		0.34		Gain of disorder (P = 0.0775)
MVP		0.29
MPC		0.14
ClinPred		0.016	T
GERP RS		-3.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.029
gMVP		0.29
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs1132312; hg19: chr1-15844615;