rs2308941

Positions:

• chr1-15518223-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001229.5(CASP9):​c.305C>T​(p.Thr102Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0147 in 1,614,176 control chromosomes in the GnomAD database, including 219 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.010 (14 hom., cov: 33)
  • Exomes 𝑓: 0.015 (205 hom.)
• Consequence: CASP9 NM_001229.5 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 0.433

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]

CASP9 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0034403205).
• BP6: Variant 1-15518223-G-A is Benign according to our data. Variant chr1-15518223-G-A is described in ClinVar as [Benign]. Clinvar id is 3042052.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0102 (1546/152284) while in subpopulation NFE AF= 0.0166 (1127/68022). AF 95% confidence interval is 0.0158. There are 14 homozygotes in gnomad4. There are 701 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1546 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CASP9	NM_001229.5	c.305C>T	p.Thr102Ile	missense_variant	2/9	ENST00000333868.10	NP_001220.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CASP9	ENST00000333868.10	c.305C>T	p.Thr102Ile	missense_variant	2/9	1	NM_001229.5	ENSP00000330237.5

Frequencies

GnomAD3 genomes AF: 0.0102 AC: 1546 AN: 152166 Hom.: 14 Cov.: 33

Gnomad AFR AF: 0.00261

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00825

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.0149

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0166

Gnomad OTH AF: 0.00766

GnomAD3 exomes AF: 0.0102 AC: 2572 AN: 251494 Hom.: 20 AF XY: 0.0101 AC XY: 1371 AN XY: 135922

Gnomad AFR exome AF: 0.00215

Gnomad AMR exome AF: 0.00535

Gnomad ASJ exome AF: 0.00129

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00131

Gnomad FIN exome AF: 0.0147

Gnomad NFE exome AF: 0.0169

Gnomad OTH exome AF: 0.0103

GnomAD4 exome AF: 0.0152 AC: 22254 AN: 1461892 Hom.: 205 Cov.: 38 AF XY: 0.0147 AC XY: 10655 AN XY: 727246

Gnomad4 AFR exome AF: 0.00206

Gnomad4 AMR exome AF: 0.00568

Gnomad4 ASJ exome AF: 0.00142

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00154

Gnomad4 FIN exome AF: 0.0149

Gnomad4 NFE exome AF: 0.0182

Gnomad4 OTH exome AF: 0.0126

GnomAD4 genome AF: 0.0102 AC: 1546 AN: 152284 Hom.: 14 Cov.: 33 AF XY: 0.00941 AC XY: 701 AN XY: 74478

Gnomad4 AFR AF: 0.00260

Gnomad4 AMR AF: 0.00824

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000830

Gnomad4 FIN AF: 0.0149

Gnomad4 NFE AF: 0.0166

Gnomad4 OTH AF: 0.00758

Alfa AF: 0.0140 Hom.: 18

Bravo AF: 0.00915

TwinsUK AF: 0.0216 AC: 80

ALSPAC AF: 0.0189 AC: 73

ESP6500AA AF: 0.00386 AC: 17

ESP6500EA AF: 0.0145 AC: 125

ExAC AF: 0.0108 AC: 1312

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.0136

EpiControl AF: 0.0140

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

CASP9-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 11, 2020

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	8.4
DANN	Benign	0.80
DEOGEN2	Benign	0.12	.;T;.;.;T;T;T
Eigen	Benign	-0.91
Eigen_PC	Benign	-0.99
FATHMM_MKL	Benign	0.093	N
LIST_S2	Benign	0.64	T;T;T;T;T;T;T
MetaRNN	Benign	0.0034	T;T;T;T;T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.0	.;L;L;.;.;.;.
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-1.1	N;N;N;N;N;N;.
REVEL	Benign	0.045
Sift	Benign	0.12	T;T;T;D;D;T;.
Sift4G	Benign	0.20	T;T;T;T;.;.;.
Polyphen		0.70	P;B;P;.;.;.;.
Vest4		0.039
MPC		0.13
ClinPred		0.0081	T
GERP RS		-1.2
Varity_R		0.053
gMVP		0.26

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

LitVar

Other links and lift over

dbSNP: rs2308941; hg19: chr1-15844718;