1-15505981-G-A

Variant names:

• chr1-15505981-G-A
• rs2308936
• NM_001229.5:c.720+9C>T

Variant summary

Our verdict is Benign. The variant received -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 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 criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.0410
• Publications: 2 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: Benign. The variant received -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 Benign. ClinVar VariationId is 777920.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 706 AD gene.

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.720+9C>T		intron	N/A	NP_001220.2
	CASP9	NM_032996.3		c.471+9C>T		intron	N/A	NP_127463.2	P55211-4
	CASP9	NM_001278054.2		c.419-10529C>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.720+9C>T		intron	N/A	ENSP00000330237.5	P55211-1
	CASP9	ENST00000348549.9	TSL:1	c.419-10529C>T		intron	N/A	ENSP00000255256.7	P55211-2
	CASP9	ENST00000400777.7	TSL:1	n.*313+9C>T		intron	N/A	ENSP00000383588.3	H0Y3S8

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

GnomAD2 exomes AF: 0.00357 AC: 896 AN: 251206 AF XY: 0.00367

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 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

African (AFR) AF: 0.000748 AC: 25 AN: 33434

American (AMR) AF: 0.00378 AC: 169 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.000230 AC: 6 AN: 26118

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.000464 AC: 40 AN: 86212

European-Finnish (FIN) AF: 0.00105 AC: 56 AN: 53398

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5764

European-Non Finnish (NFE) AF: 0.00809 AC: 8967 AN: 1109018

Other (OTH) AF: 0.00803 AC: 484 AN: 60294

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

African (AFR) AF: 0.00159 AC: 66 AN: 41576

American (AMR) AF: 0.00869 AC: 133 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4830

European-Finnish (FIN) AF: 0.000754 AC: 8 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00706 AC: 480 AN: 68034

Other (OTH) AF: 0.00664 AC: 14 AN: 2110

Alfa AF: 0.00594 Hom.: 4

Bravo AF: 0.00533

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00720

EpiControl AF: 0.00747

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	CASP9-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	11
DANN	Benign	0.44
PhyloP100		-0.041
Mutation Taster		=100/0	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: rs2308936; hg19: chr1-15832476;