6-31271640-C-A

Variant names:

• chr6-31271640-C-A
• rs2308557
• NM_002117.6:c.302G>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM1

The NM_002117.6(HLA-C):​c.302G>T​(p.Ser101Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. 13/20 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: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: HLA-C NM_002117.6 missense
• 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]

ENSG00000288813 (HGNC:):

ACMG classification

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

• PM1: In a binding_site (size 0) in uniprot entity HLAC_HUMAN

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HLA-C	NM_002117.6	c.302G>T	p.Ser101Ile	missense_variant	Exon 2 of 8	ENST00000376228.10	NP_002108.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HLA-C	ENST00000376228.10	c.302G>T	p.Ser101Ile	missense_variant	Exon 2 of 8	6	NM_002117.6	ENSP00000365402.5

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 65952 Hom.: 0 Cov.: 9

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

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

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1066260 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 535712

African (AFR) AF: 0.00 AC: 0 AN: 21002

American (AMR) AF: 0.00 AC: 0 AN: 31430

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20382

East Asian (EAS) AF: 0.00 AC: 0 AN: 28900

South Asian (SAS) AF: 0.00 AC: 0 AN: 72524

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38816

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3732

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 804868

Other (OTH) AF: 0.00 AC: 0 AN: 44606

GnomAD4 genome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 65952 Hom.: 0 Cov.: 9 AF XY: 0.00 AC XY: 0 AN XY: 31350

African (AFR) AF: 0.00 AC: 0 AN: 12832

American (AMR) AF: 0.00 AC: 0 AN: 5826

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 1756

East Asian (EAS) AF: 0.00 AC: 0 AN: 2098

South Asian (SAS) AF: 0.00 AC: 0 AN: 2024

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 4080

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 130

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 35990

Other (OTH) AF: 0.00 AC: 0 AN: 748

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	7.8
DANN	Benign	0.95
DEOGEN2	Benign	0.027	T;.
Eigen	Benign	-0.70
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.0057	N
LIST_S2	Benign	0.012	T;T
M_CAP	Benign	0.0012	T
MetaRNN	Uncertain	0.47	T;T
MetaSVM	Benign	-1.0	T
PhyloP100		-4.5
PrimateAI	Benign	0.27	T
PROVEAN	Uncertain	-3.4	D;D
REVEL	Benign	0.12
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.0070	D;D
Polyphen		0.99	D;D
Vest4		0.14
MutPred		0.33		Loss of disorder (P = 0.0014);Loss of disorder (P = 0.0014);
MVP		0.25
MPC		1.5
ClinPred		0.99	D
GERP RS		-4.1
PromoterAI		-0.012	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.48
Mutation Taster		=92/8	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: rs2308557; hg19: chr6-31239417;