rs2074491

Positions:

• chr6-31272119-T-C

Variant summary

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

The ENST00000495835.1(HLA-C):​n.12A>G variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.072 (446 hom., cov: 15)
  • Exomes 𝑓: 0.025 (1450 hom.)
• Consequence: HLA-C ENST00000495835.1 non_coding_transcript_exon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.622

Genes affected

HLA-C (HGNC:):

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 (BayesDel_noAF=-0.85).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.115 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
		n.31272119T>C		intergenic_region
HLA-C	NM_002117.6	c.-48A>G		upstream_gene_variant		ENST00000376228.10	NP_002108.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HLA-C	ENST00000376228.10	c.-48A>G		upstream_gene_variant		6	NM_002117.6	ENSP00000365402.5

Frequencies

GnomAD3 genomes AF: 0.0720 AC: 7638 AN: 106026 Hom.: 444 Cov.: 15

Gnomad AFR AF: 0.0881

Gnomad AMI AF: 0.0409

Gnomad AMR AF: 0.0646

Gnomad ASJ AF: 0.0434

Gnomad EAS AF: 0.124

Gnomad SAS AF: 0.0318

Gnomad FIN AF: 0.0820

Gnomad MID AF: 0.0620

Gnomad NFE AF: 0.0654

Gnomad OTH AF: 0.0685

GnomAD3 exomes AF: 0.160 AC: 34481 AN: 215454 Hom.: 3222 AF XY: 0.154 AC XY: 18045 AN XY: 117074

Gnomad AFR exome AF: 0.152

Gnomad AMR exome AF: 0.156

Gnomad ASJ exome AF: 0.0361

Gnomad EAS exome AF: 0.283

Gnomad SAS exome AF: 0.0774

Gnomad FIN exome AF: 0.232

Gnomad NFE exome AF: 0.163

Gnomad OTH exome AF: 0.133

GnomAD4 exome AF: 0.0246 AC: 17123 AN: 695056 Hom.: 1450 Cov.: 10 AF XY: 0.0250 AC XY: 8776 AN XY: 350960

Gnomad4 AFR exome AF: 0.0498

Gnomad4 AMR exome AF: 0.0519

Gnomad4 ASJ exome AF: 0.0259

Gnomad4 EAS exome AF: 0.101

Gnomad4 SAS exome AF: 0.0326

Gnomad4 FIN exome AF: 0.0379

Gnomad4 NFE exome AF: 0.0188

Gnomad4 OTH exome AF: 0.0290

GnomAD4 genome AF: 0.0721 AC: 7646 AN: 106120 Hom.: 446 Cov.: 15 AF XY: 0.0698 AC XY: 3533 AN XY: 50618

Gnomad4 AFR AF: 0.0879

Gnomad4 AMR AF: 0.0649

Gnomad4 ASJ AF: 0.0434

Gnomad4 EAS AF: 0.125

Gnomad4 SAS AF: 0.0324

Gnomad4 FIN AF: 0.0820

Gnomad4 NFE AF: 0.0654

Gnomad4 OTH AF: 0.0683

Alfa AF: 0.127 Hom.: 323

Asia WGS AF: 0.158 AC: 550 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	12
DANN	Benign	0.44

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs2074491; hg19: chr6-31239896;