2-201258385-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Moderate BP6_Moderate BS1

The ENST00000358485.8(CASP8):c.151+3G>A variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00119 in 1,614,068 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 0.00076 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (2 hom.)
• Consequence: CASP8 ENST00000358485.8 splice_donor_region, intron
• Scores: Splicing: ADA: 0.00004969
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.91

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]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP6: Variant 2-201258385-G-A is Benign according to our data. Variant chr2-201258385-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 870948.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000755 (115/152302) while in subpopulation NFE AF= 0.001 (68/68032). AF 95% confidence interval is 0.000808. There are 0 homozygotes in gnomad4. There are 57 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	UniProt
CASP8	NM_001080124.2	c.-26-8076G>A		intron_variant
CASP8	NM_001080125.2	c.151+3G>A		splice_donor_region_variant, intron_variant
CASP8	NM_001228.4	c.-26-8076G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CASP8	ENST00000264275.9	c.-26-8076G>A		intron_variant		1
CASP8	ENST00000358485.8	c.151+3G>A		splice_donor_region_variant, intron_variant		1
CASP8	ENST00000392258.7	c.-26-8076G>A		intron_variant		1

Frequencies

GnomAD3 genomes AF: 0.000756 AC: 115 AN: 152184 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000290

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00273

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000999

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000824 AC: 204 AN: 247476 Hom.: 0 AF XY: 0.000803 AC XY: 108 AN XY: 134476

Gnomad AFR exome AF: 0.000194

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00297

Gnomad NFE exome AF: 0.00119

Gnomad OTH exome AF: 0.000495

GnomAD4 exome AF: 0.00124 AC: 1807 AN: 1461766 Hom.: 2 Cov.: 34 AF XY: 0.00118 AC XY: 856 AN XY: 727194

Gnomad4 AFR exome AF: 0.000149

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00232

Gnomad4 NFE exome AF: 0.00144

Gnomad4 OTH exome AF: 0.00111

GnomAD4 genome AF: 0.000755 AC: 115 AN: 152302 Hom.: 0 Cov.: 32 AF XY: 0.000765 AC XY: 57 AN XY: 74464

Gnomad4 AFR AF: 0.000289

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00273

Gnomad4 NFE AF: 0.00100

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.00105 Hom.: 0

Bravo AF: 0.000635

EpiCase AF: 0.00120

EpiControl AF: 0.00113

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jul 01, 2023

CASP8: BP4 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
Cadd	Benign	16
Dann	Benign	0.84

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000050
dbscSNV1_RF	Benign	0.0040
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: rs202238412; hg19: chr2-202123108;