ENST00000392258.7:c.677C>A

Variant names:

• chr2-201276908-C-A
• rs17860424
• ENST00000392258.7:c.677C>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 4P and 2B. PM2 PM5 BP4_Moderate

The ENST00000392258.7(CASP8):​c.677C>A​(p.Thr226Lys) variant causes a missense 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. 13/17 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T226A) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CASP8 ENST00000392258.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.310
• 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)

ENSG00000289698 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-201276908-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 7760.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.07235083).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000392258.7. 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_001372051.1	MANE Select	c.742C>A	p.Arg248Arg	synonymous	Exon 7 of 9	NP_001358980.1	Q14790-1
	CASP8	NM_001400679.1		c.677C>A	p.Thr226Lys	missense	Exon 7 of 7	NP_001387608.1	Q14790-5
	CASP8	NM_001080125.2		c.919C>A	p.Arg307Arg	synonymous	Exon 7 of 9	NP_001073594.1	Q14790-9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CASP8	ENST00000392258.7	TSL:1	c.677C>A	p.Thr226Lys	missense	Exon 7 of 8	ENSP00000376087.3	Q14790-5
	CASP8	ENST00000673742.1	MANE Select	c.742C>A	p.Arg248Arg	synonymous	Exon 7 of 9	ENSP00000501268.1	Q14790-1
	CASP8	ENST00000358485.8	TSL:1	c.919C>A	p.Arg307Arg	synonymous	Exon 7 of 9	ENSP00000351273.4	Q14790-9

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Uncertain	0.060	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	11
DANN	Benign	0.75
DEOGEN2	Benign	0.012	T
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.48
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.38	T
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.072	T
MetaSVM	Benign	-1.1	T
PhyloP100		0.31
PROVEAN	Benign	0.030	N
REVEL	Benign	0.026
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.93	T
Polyphen		0.047	B
Vest4		0.24
MutPred		0.15		Gain of ubiquitination at T226 (P = 0.0039)
MVP		0.77
ClinPred		0.29	T
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=35/65	disease causing

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: rs17860424; hg19: chr2-202141631;