Genetic Variant NM_001372051.1:c.1103G>A (chr2-201285116-G-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_001372051.1(CASP8):c.1103G>A(p.Gly368Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. G368A) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

CASP8
NM_001372051.1 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.191

Publications

0 publications found

Variant links:

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

CASP8 links:

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ACMG classification

Classification was made for transcript

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

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001372051.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CASP8	NM_001372051.1	MANE Select	c.1103G>A	p.Gly368Asp	missense	Exon 8 of 9	NP_001358980.1
CASP8	NM_001080125.2		c.1280G>A	p.Gly427Asp	missense	Exon 8 of 9	NP_001073594.1
CASP8	NM_001400642.1		c.1235G>A	p.Gly412Asp	missense	Exon 7 of 8	NP_001387571.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CASP8	ENST00000673742.1	MANE Select	c.1103G>A	p.Gly368Asp	missense	Exon 8 of 9	ENSP00000501268.1
CASP8	ENST00000358485.8	TSL:1	c.1280G>A	p.Gly427Asp	missense	Exon 8 of 9	ENSP00000351273.4
CASP8	ENST00000264275.9	TSL:1	c.1154G>A	p.Gly385Asp	missense	Exon 9 of 10	ENSP00000264275.5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.91

BayesDel_addAF

Benign

-0.089

BayesDel_noAF

Benign

-0.37

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.33

Eigen

Benign

0.044

Eigen_PC

Benign

-0.17

FATHMM_MKL

Benign

0.18

LIST_S2

Benign

0.86

M_CAP

Benign

0.026

MetaRNN

Uncertain

0.65

MetaSVM

Benign

-0.97

MutationAssessor

Pathogenic

3.3

PhyloP100

0.19

PrimateAI

Benign

0.36

PROVEAN

Uncertain

-3.0

REVEL

Benign

0.20

Sift

Uncertain

0.0030

Sift4G

Benign

0.13

Polyphen

1.0

Vest4

0.46

MutPred

0.75

Gain of solvent accessibility (P = 0.0648)

MVP

0.94

MPC

1.1

ClinPred

0.96

GERP RS

1.1

Varity_R

0.69

gMVP

0.88

Mutation Taster

=67/33

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over