NM_001229.5:c.919T>G

Variant names:

• chr1-15495402-A-C
• rs750849037
• NM_001229.5:c.919T>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_001229.5(CASP9):​c.919T>G​(p.Ser307Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,455,280 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S307Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 29)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: CASP9 NM_001229.5 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.101
• Publications: 1 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 -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.047035605).
• BP6: Variant 1-15495402-A-C is Benign according to our data. Variant chr1-15495402-A-C is described in ClinVar as Likely_benign. ClinVar VariationId is 3485274.Status of the report is criteria_provided_single_submitter, 1 stars.

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.919T>G	p.Ser307Ala	missense	Exon 7 of 9	NP_001220.2
	CASP9	NM_032996.3		c.670T>G	p.Ser224Ala	missense	Exon 7 of 9	NP_127463.2	P55211-4
	CASP9	NM_001278054.2		c.469T>G	p.Ser157Ala	missense	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.919T>G	p.Ser307Ala	missense	Exon 7 of 9	ENSP00000330237.5	P55211-1
	CASP9	ENST00000348549.9	TSL:1	c.469T>G	p.Ser157Ala	missense	Exon 3 of 5	ENSP00000255256.7	P55211-2
	CASP9	ENST00000400777.7	TSL:1	n.*512T>G		non_coding_transcript_exon	Exon 7 of 9	ENSP00000383588.3	H0Y3S8

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD2 exomes AF: 0.00000418 AC: 1 AN: 239098 AF XY: 0.00000774

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000559

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1455280 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 723296

African (AFR) AF: 0.00 AC: 0 AN: 33348

American (AMR) AF: 0.00 AC: 0 AN: 43806

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25914

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39536

South Asian (SAS) AF: 0.00 AC: 0 AN: 84790

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53142

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5746

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1108806

Other (OTH) AF: 0.00 AC: 0 AN: 60192

GnomAD4 genome Cov.: 29

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Likely benign

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	0.063
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	0.097
DANN	Benign	0.32
DEOGEN2	Benign	0.058	T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.017	N
LIST_S2	Benign	0.42	T
M_CAP	Benign	0.0017	T
MetaRNN	Benign	0.047	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.030	N
PhyloP100		-0.10
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.58	N
REVEL	Benign	0.034
Sift	Benign	0.44	T
Sift4G	Benign	0.53	T
Polyphen		0.0010	B
Vest4		0.080
MutPred		0.30		Loss of phosphorylation at S307 (P = 0.0067)
MVP		0.18
MPC		0.098
ClinPred		0.030	T
GERP RS		-9.3
Varity_R		0.017
gMVP		0.18
Mutation Taster		=79/21	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: rs750849037; hg19: chr1-15821897;