rs1052571

Positions:

• chr1-15524118-G-A
• chr1-15524118-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001229.5(CASP9):​c.83C>T​(p.Ala28Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.536 in 1,537,426 control chromosomes in the GnomAD database, including 223,949 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.59 (26741 hom., cov: 32)
  • Exomes 𝑓: 0.53 (197208 hom.)
• Consequence: CASP9 NM_001229.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.25

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=5.70045E-6).
• BP6: Variant 1-15524118-G-A is Benign according to our data. Variant chr1-15524118-G-A is described in ClinVar as [Benign]. Clinvar id is 1275295.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.698 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CASP9	NM_001229.5	c.83C>T	p.Ala28Val	missense_variant	1/9	ENST00000333868.10	NP_001220.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CASP9	ENST00000333868.10	c.83C>T	p.Ala28Val	missense_variant	1/9	1	NM_001229.5	ENSP00000330237.5

Frequencies

GnomAD3 genomes AF: 0.586 AC: 88922 AN: 151748 Hom.: 26703 Cov.: 32

Gnomad AFR AF: 0.704

Gnomad AMI AF: 0.514

Gnomad AMR AF: 0.499

Gnomad ASJ AF: 0.493

Gnomad EAS AF: 0.646

Gnomad SAS AF: 0.426

Gnomad FIN AF: 0.651

Gnomad MID AF: 0.509

Gnomad NFE AF: 0.538

Gnomad OTH AF: 0.555

GnomAD3 exomes AF: 0.503 AC: 68365 AN: 135782 Hom.: 17840 AF XY: 0.499 AC XY: 36963 AN XY: 74062

Gnomad AFR exome AF: 0.685

Gnomad AMR exome AF: 0.415

Gnomad ASJ exome AF: 0.490

Gnomad EAS exome AF: 0.631

Gnomad SAS exome AF: 0.425

Gnomad FIN exome AF: 0.617

Gnomad NFE exome AF: 0.513

Gnomad OTH exome AF: 0.500

GnomAD4 exome AF: 0.530 AC: 734459 AN: 1385566 Hom.: 197208 Cov.: 52 AF XY: 0.527 AC XY: 360833 AN XY: 684316

Gnomad4 AFR exome AF: 0.703

Gnomad4 AMR exome AF: 0.426

Gnomad4 ASJ exome AF: 0.494

Gnomad4 EAS exome AF: 0.640

Gnomad4 SAS exome AF: 0.431

Gnomad4 FIN exome AF: 0.626

Gnomad4 NFE exome AF: 0.529

Gnomad4 OTH exome AF: 0.536

GnomAD4 genome AF: 0.586 AC: 89003 AN: 151860 Hom.: 26741 Cov.: 32 AF XY: 0.587 AC XY: 43516 AN XY: 74194

Gnomad4 AFR AF: 0.705

Gnomad4 AMR AF: 0.498

Gnomad4 ASJ AF: 0.493

Gnomad4 EAS AF: 0.646

Gnomad4 SAS AF: 0.424

Gnomad4 FIN AF: 0.651

Gnomad4 NFE AF: 0.538

Gnomad4 OTH AF: 0.551

Alfa AF: 0.535 Hom.: 37688

Bravo AF: 0.580

ExAC AF: 0.357 AC: 33850

Asia WGS AF: 0.542 AC: 1874 AN: 3456

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 23, 2021	This variant is associated with the following publications: (PMID: 27984487) -

CASP9-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 18, 2019

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	0.11
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	15
DANN	Uncertain	1.0
DEOGEN2	Benign	0.069	.;T;.;T
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.47
FATHMM_MKL	Benign	0.078	N
LIST_S2	Benign	0.57	T;T;T;T
MetaRNN	Benign	0.0000057	T;T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.7	.;L;L;.
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-1.1	N;N;N;N
REVEL	Benign	0.0050
Sift	Benign	0.53	T;T;T;T
Sift4G	Benign	0.13	T;T;T;.
Polyphen		0.029	B;B;P;.
Vest4		0.039
MPC		0.12
ClinPred		0.021	T
GERP RS		1.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.35
gMVP		0.11

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: rs1052571; hg19: chr1-15850613; COSMIC: COSV61600760; COSMIC: COSV61600760;