chr2-201258367-G-A

Variant names:

• chr2-201258367-G-A
• rs755371396
• ENST00000358485.8:c.136G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001080125.2(CASP8):​c.136G>A​(p.Gly46Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,718 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 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 nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: CASP8 NM_001080125.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.19
• 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0726054).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001080125.2. 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.136G>A	p.Gly46Arg	missense	Exon 1 of 9	NP_001073594.1	Q14790-9
	CASP8	NM_001400642.1		c.136G>A	p.Gly46Arg	missense	Exon 1 of 8	NP_001387571.1	A0A8Q3SID9
	CASP8	NM_001400665.1		c.136G>A	p.Gly46Arg	missense	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.136G>A	p.Gly46Arg	missense	Exon 1 of 9	ENSP00000351273.4	Q14790-9
	CASP8	ENST00000264275.9	TSL:1	c.-26-8094G>A		intron	N/A	ENSP00000264275.5	Q14790-4
	CASP8	ENST00000392258.7	TSL:1	c.-26-8094G>A		intron	N/A	ENSP00000376087.3	Q14790-5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461718 Hom.: 0 Cov.: 34 AF XY: 0.00000275 AC XY: 2 AN XY: 727168

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111888

Other (OTH) AF: 0.00 AC: 0 AN: 60378

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	11
DANN	Uncertain	0.99
Eigen	Benign	-0.91
Eigen_PC	Benign	-0.97
FATHMM_MKL	Benign	0.038	N
LIST_S2	Benign	0.52	T
M_CAP	Benign	0.0025	T
MetaRNN	Benign	0.073	T
MetaSVM	Benign	-0.96	T
PhyloP100		1.2
PrimateAI	Benign	0.34	T
PROVEAN	Benign	0.35	N
REVEL	Benign	0.047
Sift	Benign	0.038	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.023	B
Vest4		0.26
MutPred		0.26		Loss of ubiquitination at K47 (P = 0.0634)
MVP		0.36
MPC		0.67
ClinPred		0.90	D
GERP RS		1.9
PromoterAI		-0.021	Neutral
gMVP		0.046
Mutation Taster		=100/0	polymorphism

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: rs755371396; hg19: chr2-202123090;