rs11897628

Positions:

• chr2-201269598-T-C

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS1

The NM_001228.5(CASP8):​c.394T>C​(p.Leu132Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000677 in 1,610,734 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0039 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00034 (1 hom.)
• Consequence: CASP8 NM_001228.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.606

Genes affected

CASP8 (HGNC:1509): (caspase 8) 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 composed of a prodomain, a large protease subunit, and a small protease subunit. Activation of caspases requires proteolytic processing at conserved internal aspartic residues to generate a heterodimeric enzyme consisting of the large and small subunits. This protein is involved in the programmed cell death induced by Fas and various apoptotic stimuli. The N-terminal FADD-like death effector domain of this protein suggests that it may interact with Fas-interacting protein FADD. This protein was detected in the insoluble fraction of the affected brain region from Huntington disease patients but not in those from normal controls, which implicated the role in neurodegenerative diseases. Many alternatively spliced transcript variants encoding different isoforms have been described, although not all variants have had their full-length sequences determined. [provided by RefSeq, Jul 2008]

CASP8 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 2-201269598-T-C is Benign according to our data. Variant chr2-201269598-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 333497.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-201269598-T-C is described in Lovd as [Benign]. Variant chr2-201269598-T-C is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.606 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00389 (593/152286) while in subpopulation AFR AF= 0.0139 (579/41556). AF 95% confidence interval is 0.013. There are 1 homozygotes in gnomad4. There are 291 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CASP8	NM_001372051.1	c.306-1918T>C		intron_variant		ENST00000673742.1	NP_001358980.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CASP8	ENST00000673742.1	c.306-1918T>C		intron_variant			NM_001372051.1	ENSP00000501268.1

Frequencies

GnomAD3 genomes AF: 0.00389 AC: 592 AN: 152168 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0139

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.000780 AC: 193 AN: 247510 Hom.: 1 AF XY: 0.000544 AC XY: 73 AN XY: 134166

Gnomad AFR exome AF: 0.0115

Gnomad AMR exome AF: 0.000350

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000331

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000178

Gnomad OTH exome AF: 0.000333

GnomAD4 exome AF: 0.000341 AC: 497 AN: 1458448 Hom.: 1 Cov.: 29 AF XY: 0.000291 AC XY: 211 AN XY: 725674

Gnomad4 AFR exome AF: 0.0126

Gnomad4 AMR exome AF: 0.000471

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000811

Gnomad4 OTH exome AF: 0.000713

GnomAD4 genome AF: 0.00389 AC: 593 AN: 152286 Hom.: 1 Cov.: 32 AF XY: 0.00391 AC XY: 291 AN XY: 74478

Gnomad4 AFR AF: 0.0139

Gnomad4 AMR AF: 0.000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.00220 Hom.: 0

Bravo AF: 0.00368

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autoimmune lymphoproliferative syndrome type 2B Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 19, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 24, 2019	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

not specified Benign:1

Benign, no assertion criteria provided

clinical testing

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	1.1
DANN	Benign	0.34

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: rs11897628; hg19: chr2-202134321;