chr2-86790452-C-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001768.7(CD8A):​c.279G>T​(p.Arg93Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000471 in 1,614,058 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 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. R93K) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000047 ( 1 hom. )

Consequence

CD8A
NM_001768.7 missense

Scores

1
4
14

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.158
Variant links:
Genes affected
CD8A (HGNC:1706): (CD8 subunit alpha) The CD8 antigen is a cell surface glycoprotein found on most cytotoxic T lymphocytes that mediates efficient cell-cell interactions within the immune system. The CD8 antigen acts as a coreceptor with the T-cell receptor on the T lymphocyte to recognize antigens displayed by an antigen presenting cell in the context of class I MHC molecules. The coreceptor functions as either a homodimer composed of two alpha chains or as a heterodimer composed of one alpha and one beta chain. Both alpha and beta chains share significant homology to immunoglobulin variable light chains. This gene encodes the CD8 alpha chain. Multiple transcript variants encoding different isoforms have been found for this gene. The major protein isoforms of this gene differ by the presence or absence of a transmembrane domain and thus differ in being a membrane-anchored or secreted protein. [provided by RefSeq, May 2020]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.036940813).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
CD8ANM_001768.7 linkuse as main transcriptc.279G>T p.Arg93Ser missense_variant 2/6 ENST00000283635.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
CD8AENST00000283635.8 linkuse as main transcriptc.279G>T p.Arg93Ser missense_variant 2/61 NM_001768.7 P1P01732-1

Frequencies

GnomAD3 genomes
AF:
0.0000460
AC:
7
AN:
152218
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00173
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000956
AC:
24
AN:
250974
Hom.:
0
AF XY:
0.0000957
AC XY:
13
AN XY:
135826
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00199
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000265
Gnomad OTH exome
AF:
0.000163
GnomAD4 exome
AF:
0.0000472
AC:
69
AN:
1461840
Hom.:
1
Cov.:
34
AF XY:
0.0000481
AC XY:
35
AN XY:
727218
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00199
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000989
Gnomad4 OTH exome
AF:
0.0000993
GnomAD4 genome
AF:
0.0000460
AC:
7
AN:
152218
Hom.:
0
Cov.:
32
AF XY:
0.0000403
AC XY:
3
AN XY:
74372
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00173
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000235
Hom.:
94
Bravo
AF:
0.0000642
ExAC
AF:
0.0000659
AC:
8
EpiCase
AF:
0.0000545
EpiControl
AF:
0.00

ClinVar

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

Submissions by phenotype

Susceptibility to respiratory infections associated with CD8alpha chain mutation Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpNov 13, 2021This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 93 of the CD8A protein (p.Arg93Ser). This variant is present in population databases (rs2229240, gnomAD 0.2%). This variant has not been reported in the literature in individuals affected with CD8A-related conditions. ClinVar contains an entry for this variant (Variation ID: 843539). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.64
BayesDel_addAF
Benign
-0.21
T
BayesDel_noAF
Benign
-0.47
CADD
Benign
17
DANN
Benign
0.96
DEOGEN2
Uncertain
0.65
.;D;D;T
Eigen
Benign
-0.50
Eigen_PC
Benign
-0.63
FATHMM_MKL
Benign
0.084
N
LIST_S2
Benign
0.69
T;.;T;T
M_CAP
Benign
0.045
D
MetaRNN
Benign
0.037
T;T;T;T
MetaSVM
Benign
-0.91
T
MutationAssessor
Benign
1.0
L;L;L;.
MutationTaster
Benign
1.0
N;N;N;N;N;N
PrimateAI
Benign
0.29
T
PROVEAN
Uncertain
-3.1
D;D;D;D
REVEL
Benign
0.069
Sift
Uncertain
0.0050
D;D;D;D
Sift4G
Uncertain
0.014
D;D;D;D
Polyphen
0.38
B;P;P;.
Vest4
0.18
MutPred
0.47
Gain of ubiquitination at K92 (P = 0.0495);Gain of ubiquitination at K92 (P = 0.0495);Gain of ubiquitination at K92 (P = 0.0495);Gain of ubiquitination at K92 (P = 0.0495);
MVP
0.88
MPC
1.1
ClinPred
0.18
T
GERP RS
2.9
Varity_R
0.60
gMVP
0.54

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: rs2229240; hg19: chr2-87017575; API