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GeneBe

rs1045485

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001372051.1(CASP8):c.853G>A(p.Asp285Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000658 in 152058 control chromosomes in the gnomAD Genomes 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. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D285H) has been classified as Benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000040 ( 0 hom. )

Consequence

CASP8
NM_001372051.1 missense

Scores

17

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.867

Links

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BP4
?
Computational evidence support a benign effect (MetaRNN=0.057195336).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
CASP8NM_001372051.1 linkuse as main transcriptc.853G>A p.Asp285Asn missense_variant 8/9 ENST00000673742.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
CASP8ENST00000673742.1 linkuse as main transcriptc.853G>A p.Asp285Asn missense_variant 8/9 NM_001372051.1 P1Q14790-1

Frequencies

GnomAD3 genomes
AF:
0.00000658
AC:
1
AN:
152058
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000193
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000398
AC:
1
AN:
251456
Hom.:
0
AF XY:
0.00000736
AC XY:
1
AN XY:
135908
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000544
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000410
AC:
6
AN:
1461876
Hom.:
0
AF XY:
0.00000275
AC XY:
2
AN XY:
727244
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000504
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000270
Gnomad4 OTH exome
AF:
0.00
Bravo
AF:
0.00000756

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Autoimmune lymphoproliferative syndrome type 2B Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingInvitaeJul 19, 2022This variant is present in population databases (no rsID available, gnomAD 0.006%). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The asparagine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. ClinVar contains an entry for this variant (Variation ID: 1347161). This variant has not been reported in the literature in individuals affected with CASP8-related conditions. This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 302 of the CASP8 protein (p.Asp302Asn). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.069
BayesDel_addAF
Benign
-0.53
T
BayesDel_noAF
Benign
-0.83
Cadd
Benign
0.053
Dann
Benign
0.51
Eigen
Benign
-1.8
Eigen_PC
Benign
-1.7
FATHMM_MKL
Benign
0.0098
N
LIST_S2
Benign
0.19
T;T;T;T;T;T
M_CAP
Benign
0.0028
T
MetaRNN
Benign
0.057
T;T;T;T;T;T
MetaSVM
Benign
-0.95
T
MutationTaster
Benign
1.0
N;N;N;N;N;N;N
PrimateAI
Benign
0.26
T
PROVEAN
Benign
0.56
N;N;N;N;N;N
REVEL
Benign
0.025
Sift
Benign
0.65
T;T;T;T;T;T
Sift4G
Benign
0.99
T;T;T;T;T;T
Polyphen
0.0
B;B;B;B;B;.
Vest4
0.11
MutPred
0.38
.;Loss of ubiquitination at K282 (P = 0.1446);.;.;.;.;
MVP
0.55
MPC
0.29
ClinPred
0.024
T
GERP RS
-3.4
Varity_R
0.16
gMVP
0.31

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1045485; hg19: chr2-202149589; COSMIC: COSV51853588; COSMIC: COSV51853588; API