6-31271724-G-T

Variant names:

• chr6-31271724-G-T
• rs1050409
• NM_002117.6:c.218C>A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002117.6(HLA-C):​c.218C>A​(p.Ala73Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0617 in 1,388,764 control chromosomes in the GnomAD database, including 9,180 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/18 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

• Frequency:
  • Genomes: 𝑓 0.035 (107 hom., cov: 14)
  • Exomes 𝑓: 0.064 (9073 hom.)
• Consequence: HLA-C NM_002117.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.366

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0017168224).
• BA1: GnomAdExome4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.155 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HLA-C	NM_002117.6	c.218C>A	p.Ala73Glu	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.218C>A	p.Ala73Glu	missense_variant	Exon 2 of 8	6	NM_002117.6	ENSP00000365402.5

Frequencies

GnomAD3 genomes AF: 0.0346 AC: 3209 AN: 92844 Hom.: 107 Cov.: 14

Gnomad AFR AF: 0.0486

Gnomad AMI AF: 0.0503

Gnomad AMR AF: 0.0358

Gnomad ASJ AF: 0.0719

Gnomad EAS AF: 0.0116

Gnomad SAS AF: 0.0226

Gnomad FIN AF: 0.0365

Gnomad MID AF: 0.0598

Gnomad NFE AF: 0.0279

Gnomad OTH AF: 0.0411

GnomAD3 exomes AF: 0.130 AC: 32609 AN: 250518 Hom.: 2517 AF XY: 0.128 AC XY: 17366 AN XY: 135638

Gnomad AFR exome AF: 0.200

Gnomad AMR exome AF: 0.188

Gnomad ASJ exome AF: 0.197

Gnomad EAS exome AF: 0.0487

Gnomad SAS exome AF: 0.118

Gnomad FIN exome AF: 0.169

Gnomad NFE exome AF: 0.106

Gnomad OTH exome AF: 0.126

GnomAD4 exome AF: 0.0636 AC: 82475 AN: 1295860 Hom.: 9073 Cov.: 39 AF XY: 0.0656 AC XY: 42431 AN XY: 646730

Gnomad4 AFR exome AF: 0.159

Gnomad4 AMR exome AF: 0.153

Gnomad4 ASJ exome AF: 0.156

Gnomad4 EAS exome AF: 0.0330

Gnomad4 SAS exome AF: 0.0901

Gnomad4 FIN exome AF: 0.127

Gnomad4 NFE exome AF: 0.0509

Gnomad4 OTH exome AF: 0.0689

GnomAD4 genome AF: 0.0346 AC: 3216 AN: 92904 Hom.: 107 Cov.: 14 AF XY: 0.0345 AC XY: 1547 AN XY: 44810

Gnomad4 AFR AF: 0.0487

Gnomad4 AMR AF: 0.0359

Gnomad4 ASJ AF: 0.0719

Gnomad4 EAS AF: 0.0117

Gnomad4 SAS AF: 0.0226

Gnomad4 FIN AF: 0.0365

Gnomad4 NFE AF: 0.0279

Gnomad4 OTH AF: 0.0407

Alfa AF: 0.106 Hom.: 446

TwinsUK AF: 0.0785 AC: 291

ALSPAC AF: 0.0838 AC: 323

ESP6500AA AF: 0.190 AC: 574

ESP6500EA AF: 0.113 AC: 610

ExAC AF: 0.129 AC: 15601

Asia WGS AF: 0.112 AC: 392 AN: 3476

EpiCase AF: 0.119

EpiControl AF: 0.128

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	19
DANN	Benign	0.93
DEOGEN2	Benign	0.021	T;.
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.46
FATHMM_MKL	Benign	0.036	N
LIST_S2	Benign	0.39	T;T
MetaRNN	Benign	0.0017	T;T
MetaSVM	Benign	-1.1	T
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-3.4	D;D
REVEL	Benign	0.15
Sift	Benign	0.043	D;D
Sift4G	Uncertain	0.023	D;D
Polyphen		0.022	B;B
Vest4		0.10
MPC		0.61
ClinPred		0.10	T
GERP RS		1.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.59

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

Other links and lift over

dbSNP: rs1050409; hg19: chr6-31239501; COSMIC: COSV66115644; COSMIC: COSV66115644;