1-15506048-T-A

Variant names:

• chr1-15506048-T-A
• rs1052576
• NM_001229.5:c.662A>T

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.662A>T​(p.Gln221Leu) 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q221R) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CASP9 NM_001229.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.88
• Publications: 84 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=0.12094173).

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.662A>T	p.Gln221Leu	missense	Exon 5 of 9	NP_001220.2
	CASP9	NM_032996.3		c.413A>T	p.Gln138Leu	missense	Exon 5 of 9	NP_127463.2	P55211-4
	CASP9	NM_001278054.2		c.419-10596A>T		intron	N/A	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.662A>T	p.Gln221Leu	missense	Exon 5 of 9	ENSP00000330237.5	P55211-1
	CASP9	ENST00000348549.9	TSL:1	c.419-10596A>T		intron	N/A	ENSP00000255256.7	P55211-2
	CASP9	ENST00000400777.7	TSL:1	n.*255A>T		non_coding_transcript_exon	Exon 5 of 9	ENSP00000383588.3	H0Y3S8

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1461710 Hom.: 0 Cov.: 41 AF XY: 0.00 AC XY: 0 AN XY: 727166

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53398

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111872

Other (OTH) AF: 0.00 AC: 0 AN: 60386

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 47168

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	0.073
DANN	Benign	0.71
DEOGEN2	Benign	0.18	T
Eigen	Benign	-1.9
Eigen_PC	Benign	-2.0
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.41	T
M_CAP	Benign	0.0046	T
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	L
PhyloP100		-1.9
PrimateAI	Benign	0.23	T
PROVEAN	Uncertain	-3.3	D
REVEL	Benign	0.081
Sift	Benign	0.035	D
Sift4G	Uncertain	0.053	T
Polyphen		0.082	B
Vest4		0.30
MutPred		0.48		Loss of helix (P = 0.1299)
MVP		0.12
MPC		0.13
ClinPred		0.14	T
GERP RS		-9.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.10
gMVP		0.48
Mutation Taster		=84/16	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: rs1052576; hg19: chr1-15832543;