rs9264638

chr6-31270541-G-Achr6-31270541-G-Cchr6-31270541-G-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The NM_002117.6(HLA-C):c.620-56C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00151 in 54,846 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.0015 (0 hom., cov: 2)
  • Exomes 𝑓: 0.0018 (135 hom.)
  • Failed GnomAD Quality Control
• Consequence: HLA-C NM_002117.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.25

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 Likely_benign. Variant got -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HLA-C	NM_002117.6	c.620-56C>T		intron_variant		ENST00000376228.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HLA-C	ENST00000376228.10	c.620-56C>T		intron_variant			NM_002117.6	P4

Frequencies

GnomAD3 genomes AF: 0.00151 AC: 83 AN: 54806 Hom.: 0 Cov.: 2

Gnomad AFR AF: 0.00244

Gnomad AMI AF: 0.00467

Gnomad AMR AF: 0.00268

Gnomad ASJ AF: 0.00138

Gnomad EAS AF: 0.000729

Gnomad SAS AF: 0.00201

Gnomad FIN AF: 0.000751

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00108

Gnomad OTH AF: 0.00156

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00175 AC: 1218 AN: 694688 Hom.: 135 Cov.: 10 AF XY: 0.00223 AC XY: 766 AN XY: 342974

Gnomad4 AFR exome AF: 0.00554

Gnomad4 AMR exome AF: 0.00370

Gnomad4 ASJ exome AF: 0.00438

Gnomad4 EAS exome AF: 0.00246

Gnomad4 SAS exome AF: 0.00999

Gnomad4 FIN exome AF: 0.00419

Gnomad4 NFE exome AF: 0.000956

Gnomad4 OTH exome AF: 0.00207

GnomAD4 genome AF: 0.00151 AC: 83 AN: 54846 Hom.: 0 Cov.: 2 AF XY: 0.00177 AC XY: 46 AN XY: 26044

Gnomad4 AFR AF: 0.00243

Gnomad4 AMR AF: 0.00268

Gnomad4 ASJ AF: 0.00138

Gnomad4 EAS AF: 0.000736

Gnomad4 SAS AF: 0.00201

Gnomad4 FIN AF: 0.000751

Gnomad4 NFE AF: 0.00108

Gnomad4 OTH AF: 0.00154

Alfa AF: 0.303 Hom.: 1012

Asia WGS AF: 0.758 AC: 2637 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
Cadd	Benign	4.3
Dann	Benign	0.62

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: rs9264638; hg19: chr6-31238318; COSMIC: COSV66112539; COSMIC: COSV66112539;