1-15505981-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001229.5(CASP9):c.720+9C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00649 in 1,610,982 control chromosomes in the GnomAD database, including 63 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0046 (4 hom., cov: 33)
  • Exomes 𝑓: 0.0067 (59 hom.)
• Consequence: CASP9 NM_001229.5 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0410

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 Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 1-15505981-G-A is Benign according to our data. Variant chr1-15505981-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 777920.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd at 706 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CASP9	NM_001229.5	c.720+9C>T		intron_variant		ENST00000333868.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CASP9	ENST00000333868.10	c.720+9C>T		intron_variant		1	NM_001229.5	P1

Frequencies

GnomAD3 genomes AF: 0.00464 AC: 706 AN: 152218 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.00159

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00870

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.000754

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00705

Gnomad OTH AF: 0.00670

GnomAD3 exomes AF: 0.00357 AC: 896 AN: 251206 Hom.: 4 AF XY: 0.00367 AC XY: 498 AN XY: 135830

Gnomad AFR exome AF: 0.00154

Gnomad AMR exome AF: 0.00324

Gnomad ASJ exome AF: 0.000199

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000523

Gnomad FIN exome AF: 0.00106

Gnomad NFE exome AF: 0.00604

Gnomad OTH exome AF: 0.00522

GnomAD4 exome AF: 0.00668 AC: 9749 AN: 1458646 Hom.: 59 Cov.: 29 AF XY: 0.00648 AC XY: 4705 AN XY: 725924

Gnomad4 AFR exome AF: 0.000748

Gnomad4 AMR exome AF: 0.00378

Gnomad4 ASJ exome AF: 0.000230

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000464

Gnomad4 FIN exome AF: 0.00105

Gnomad4 NFE exome AF: 0.00809

Gnomad4 OTH exome AF: 0.00803

GnomAD4 genome AF: 0.00463 AC: 706 AN: 152336 Hom.: 4 Cov.: 33 AF XY: 0.00388 AC XY: 289 AN XY: 74490

Gnomad4 AFR AF: 0.00159

Gnomad4 AMR AF: 0.00869

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.000754

Gnomad4 NFE AF: 0.00706

Gnomad4 OTH AF: 0.00664

Alfa AF: 0.00584 Hom.: 3

Bravo AF: 0.00533

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00720

EpiControl AF: 0.00747

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

CASP9-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 09, 2019

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

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
Cadd	Benign	11
Dann	Benign	0.44

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: rs2308936; hg19: chr1-15832476;