ENST00000358485.8:c.30T>G

Variant names:

• chr2-201258261-T-G
• ENST00000358485.8:c.30T>G

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 2P and 7B. PM2 BP4_Strong BP6_Moderate BP7

The ENST00000358485.8(CASP8):​c.30T>G​(p.Val10Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.00020 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CASP8 ENST00000358485.8 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.51
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• autoimmune lymphoproliferative syndrome type 2B

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 2-201258261-T-G is Benign according to our data. Variant chr2-201258261-T-G is described in ClinVar as Likely_benign. ClinVar VariationId is 2651816.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-1.51 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000358485.8. 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
	CASP8	NM_001080125.2		c.30T>G	p.Val10Val	synonymous	Exon 1 of 9	NP_001073594.1	Q14790-9
	CASP8	NM_001400642.1		c.30T>G	p.Val10Val	synonymous	Exon 1 of 8	NP_001387571.1	A0A8Q3SID9
	CASP8	NM_001400665.1		c.30T>G	p.Val10Val	synonymous	Exon 1 of 6	NP_001387594.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CASP8	ENST00000358485.8	TSL:1	c.30T>G	p.Val10Val	synonymous	Exon 1 of 9	ENSP00000351273.4	Q14790-9
	CASP8	ENST00000264275.9	TSL:1	c.-26-8200T>G		intron	N/A	ENSP00000264275.5	Q14790-4
	CASP8	ENST00000392258.7	TSL:1	c.-26-8200T>G		intron	N/A	ENSP00000376087.3	Q14790-5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000199 AC: 288 AN: 1448308 Hom.: 0 Cov.: 30 AF XY: 0.000175 AC XY: 126 AN XY: 720712

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000180 AC: 6 AN: 33338

American (AMR) AF: 0.0000225 AC: 1 AN: 44510

Ashkenazi Jewish (ASJ) AF: 0.000115 AC: 3 AN: 26012

East Asian (EAS) AF: 0.00 AC: 0 AN: 39658

South Asian (SAS) AF: 0.000139 AC: 12 AN: 86122

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53362

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5738

European-Non Finnish (NFE) AF: 0.000232 AC: 255 AN: 1099680

Other (OTH) AF: 0.000184 AC: 11 AN: 59888

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	1.5
DANN	Benign	0.48
PhyloP100		-1.5
PromoterAI		-0.091	Neutral
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

hg19: chr2-202122984;