1-15524569-ATCCCCGCACTGACCTCACG-ATCCCCGCACTGACCTCACGTCCCCGCACTGACCTCACG

Variant names:

• chr1-15524569-A-ATCCCCGCACTGACCTCACG
• rs4645982
• NM_032996.3:c.-123_-118+13dupCGTGAGGTCAGTGCGGGGA

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

The NM_032996.3(CASP9):​c.-123_-118+13dupCGTGAGGTCAGTGCGGGGA variant causes a intron change involving the alteration of a non-conserved nucleotide. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.51 (5867 hom., cov: 0)
  • Exomes 𝑓: 0.52 (45072 hom.)
  • Failed GnomAD Quality Control
• Consequence: CASP9 NM_032996.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.490
• Publications: 12 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 -8 ACMG points.

• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.605 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032996.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CASP9	NM_032996.3		c.-123_-118+13dupCGTGAGGTCAGTGCGGGGA		intron	N/A	NP_127463.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CASP9	ENST00000375890.8	TSL:2	c.-118+13_-118+14insCGTGAGGTCAGTGCGGGGA		intron	N/A	ENSP00000365051.4
	CASP9	ENST00000447522.5	TSL:3	c.-118+282_-118+283insCGTGAGGTCAGTGCGGGGA		intron	N/A	ENSP00000396540.1
	CASP9	ENST00000469637.1	TSL:3	c.-239+1621_-239+1622insCGTGAGGTCAGTGCGGGGA		intron	N/A	ENSP00000480785.1

Frequencies

GnomAD3 genomes AF: 0.506 AC: 25666 AN: 50690 Hom.: 5861 Cov.: 0

Gnomad AFR AF: 0.617

Gnomad AMI AF: 0.386

Gnomad AMR AF: 0.465

Gnomad ASJ AF: 0.442

Gnomad EAS AF: 0.557

Gnomad SAS AF: 0.339

Gnomad FIN AF: 0.571

Gnomad MID AF: 0.414

Gnomad NFE AF: 0.477

Gnomad OTH AF: 0.463

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.521 AC: 146359 AN: 281060 Hom.: 45072 Cov.: 8 AF XY: 0.514 AC XY: 70902 AN XY: 138022

African (AFR) AF: 0.734 AC: 3451 AN: 4702

American (AMR) AF: 0.394 AC: 212 AN: 538

Ashkenazi Jewish (ASJ) AF: 0.418 AC: 1142 AN: 2734

East Asian (EAS) AF: 0.609 AC: 706 AN: 1160

South Asian (SAS) AF: 0.370 AC: 7634 AN: 20646

European-Finnish (FIN) AF: 0.557 AC: 2804 AN: 5036

Middle Eastern (MID) AF: 0.386 AC: 273 AN: 708

European-Non Finnish (NFE) AF: 0.531 AC: 124707 AN: 234906

Other (OTH) AF: 0.511 AC: 5430 AN: 10630

GnomAD4 genome AF: 0.506 AC: 25672 AN: 50690 Hom.: 5867 Cov.: 0 AF XY: 0.510 AC XY: 11899 AN XY: 23322

African (AFR) AF: 0.617 AC: 6673 AN: 10812

American (AMR) AF: 0.465 AC: 2098 AN: 4510

Ashkenazi Jewish (ASJ) AF: 0.442 AC: 709 AN: 1604

East Asian (EAS) AF: 0.559 AC: 899 AN: 1608

South Asian (SAS) AF: 0.335 AC: 410 AN: 1224

European-Finnish (FIN) AF: 0.571 AC: 1034 AN: 1810

Middle Eastern (MID) AF: 0.414 AC: 24 AN: 58

European-Non Finnish (NFE) AF: 0.477 AC: 13417 AN: 28146

Other (OTH) AF: 0.465 AC: 317 AN: 682

Alfa AF: 0.342 Hom.: 843

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.49
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs4645982; hg19: chr1-15851064;