1-15495437-C-G

Position:

• chr1-15495437-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001229.5(CASP9):​c.884G>C​(p.Gly295Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000000692 in 1,444,546 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 29)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: CASP9 NM_001229.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.83

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

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.848

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CASP9	NM_001229.5	c.884G>C	p.Gly295Ala	missense_variant	7/9	ENST00000333868.10	NP_001220.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CASP9	ENST00000333868.10	c.884G>C	p.Gly295Ala	missense_variant	7/9	1	NM_001229.5	ENSP00000330237	P1

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome AF: 6.92e-7 AC: 1 AN: 1444546 Hom.: 0 Cov.: 31 AF XY: 0.00000139 AC XY: 1 AN XY: 717226

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000120

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 29

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 20, 2024

The c.884G>C (p.G295A) alteration is located in exon 7 (coding exon 7) of the CASP9 gene. This alteration results from a G to C substitution at nucleotide position 884, causing the glycine (G) at amino acid position 295 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.47
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.060
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.28	.;T;.;.;T
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	D;D;D;D;D
M_CAP	Benign	0.063	D
MetaRNN	Pathogenic	0.85	D;D;D;D;D
MetaSVM	Benign	-0.84	T
MutationAssessor	Pathogenic	3.0	.;M;.;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.48	T
PROVEAN	Pathogenic	-5.5	D;D;D;D;D
REVEL	Uncertain	0.39
Sift	Uncertain	0.0030	D;D;D;D;D
Sift4G	Benign	0.10	T;D;D;D;.
Polyphen		1.0	D;D;D;.;.
Vest4		0.77
MutPred		0.71		Gain of sheet (P = 0.039);Gain of sheet (P = 0.039);.;.;.;
MVP		0.82
MPC		0.58
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.90
gMVP		0.59

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-15821932;