6-31271640-C-G
Variant names:
Variant summary
Our verdict is Uncertain significance. The variant received 2 ACMG points: 4P and 2B. PM1PM2BP4_Moderate
The NM_002117.6(HLA-C):c.302G>C(p.Ser101Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000469 in 1,066,242 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.
Frequency
Genomes: 𝑓 0.0 ( 0 hom., cov: 9)
Exomes 𝑓: 0.0000047 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
HLA-C
NM_002117.6 missense
NM_002117.6 missense
Scores
2
16
Clinical Significance
Not reported in ClinVar
Conservation
PhyloP100: -4.50
Publications
29 publications found
Genes affected
HLA-C (HGNC:4933): (major histocompatibility complex, class I, C) HLA-C belongs to the HLA class I heavy chain paralogues. This class I molecule is a heterodimer consisting of a heavy chain and a light chain (beta-2 microglobulin). The heavy chain is anchored in the membrane. Class I molecules play a central role in the immune system by presenting peptides derived from endoplasmic reticulum lumen. They are expressed in nearly all cells. The heavy chain is approximately 45 kDa and its gene contains 8 exons. Exon one encodes the leader peptide, exons 2 and 3 encode the alpha1 and alpha2 domain, which both bind the peptide, exon 4 encodes the alpha3 domain, exon 5 encodes the transmembrane region, and exons 6 and 7 encode the cytoplasmic tail. Polymorphisms within exon 2 and exon 3 are responsible for the peptide binding specificity of each class one molecule. Typing for these polymorphisms is routinely done for bone marrow and kidney transplantation. About 6000 HLA-C alleles have been described. The HLA system plays an important role in the occurrence and outcome of infectious diseases, including those caused by the malaria parasite, the human immunodeficiency virus (HIV), and the severe acute respiratory syndrome coronavirus (SARS-CoV). The structural spike and the nucleocapsid proteins of the novel coronavirus SARS-CoV-2, which causes coronavirus disease 2019 (COVID-19), are reported to contain multiple Class I epitopes with predicted HLA restrictions. Individual HLA genetic variation may help explain different immune responses to a virus across a population.[provided by RefSeq, Aug 2020]
Genome browser will be placed here
ACMG classification
Classification was made for transcript
Our verdict: Uncertain_significance. The variant received 2 ACMG points.
PM1
In a binding_site (size 0) in uniprot entity HLAC_HUMAN
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.23850495).
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes 0.00 AC: 0AN: 65952Hom.: 0 Cov.: 9
GnomAD3 genomes
AF:
AC:
0
AN:
65952
Hom.:
Cov.:
9
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD4 exome AF: 0.00000469 AC: 5AN: 1066242Hom.: 0 Cov.: 32 AF XY: 0.00000373 AC XY: 2AN XY: 535698 show subpopulations ⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
GnomAD4 exome
AF:
AC:
5
AN:
1066242
Hom.:
Cov.:
32
AF XY:
AC XY:
2
AN XY:
535698
show subpopulations
⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
African (AFR)
AF:
AC:
0
AN:
21002
American (AMR)
AF:
AC:
0
AN:
31430
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
20378
East Asian (EAS)
AF:
AC:
0
AN:
28900
South Asian (SAS)
AF:
AC:
0
AN:
72524
European-Finnish (FIN)
AF:
AC:
1
AN:
38812
Middle Eastern (MID)
AF:
AC:
0
AN:
3732
European-Non Finnish (NFE)
AF:
AC:
3
AN:
804860
Other (OTH)
AF:
AC:
1
AN:
44604
⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.235
Heterozygous variant carriers
0
1
2
3
4
5
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
GnomAD4 genome 0.00 AC: 0AN: 66014Hom.: 0 Cov.: 9 AF XY: 0.00 AC XY: 0AN XY: 31430
GnomAD4 genome
Data not reliable, filtered out with message: AC0
AF:
AC:
0
AN:
66014
Hom.:
Cov.:
9
AF XY:
AC XY:
0
AN XY:
31430
African (AFR)
AF:
AC:
0
AN:
12886
American (AMR)
AF:
AC:
0
AN:
5830
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
1756
East Asian (EAS)
AF:
AC:
0
AN:
2086
South Asian (SAS)
AF:
AC:
0
AN:
2032
European-Finnish (FIN)
AF:
AC:
0
AN:
4080
Middle Eastern (MID)
AF:
AC:
0
AN:
124
European-Non Finnish (NFE)
AF:
AC:
0
AN:
35990
Other (OTH)
AF:
AC:
0
AN:
762
Alfa
AF:
Hom.:
ClinVar
Not reported inComputational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
DANN
Benign
DEOGEN2
Benign
T;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
N
LIST_S2
Benign
T;T
M_CAP
Benign
T
MetaRNN
Benign
T;T
MetaSVM
Benign
T
PhyloP100
PrimateAI
Benign
T
PROVEAN
Benign
N;N
REVEL
Benign
Sift
Uncertain
D;D
Sift4G
Uncertain
D;D
Polyphen
B;B
Vest4
MutPred
Loss of disorder (P = 0.0817);Loss of disorder (P = 0.0817);
MVP
MPC
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.