chr6-31271729-C-G

Variant names:

• chr6-31271729-C-G
• rs1050414
• NM_002117.6:c.213G>C

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Moderate BP7 BA1

The NM_002117.6(HLA-C):​c.213G>C​(p.Pro71Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.126 in 1,460,664 control chromosomes in the GnomAD database, including 30,929 homozygotes. 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 0.17 (3367 hom., cov: 15)
  • Exomes 𝑓: 0.12 (27562 hom.)
• Consequence: HLA-C NM_002117.6 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.822
• Publications: 22 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: Benign. The variant received -11 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.023).
• BP7: Synonymous conserved (PhyloP=-0.822 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.22 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HLA-C	NM_002117.6	c.213G>C	p.Pro71Pro	synonymous_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.213G>C	p.Pro71Pro	synonymous_variant	Exon 2 of 8	6	NM_002117.6	ENSP00000365402.5

Frequencies

GnomAD3 genomes AF: 0.168 AC: 16494 AN: 98442 Hom.: 3363 Cov.: 15

Gnomad AFR AF: 0.225

Gnomad AMI AF: 0.280

Gnomad AMR AF: 0.135

Gnomad ASJ AF: 0.161

Gnomad EAS AF: 0.0747

Gnomad SAS AF: 0.172

Gnomad FIN AF: 0.134

Gnomad MID AF: 0.245

Gnomad NFE AF: 0.155

Gnomad OTH AF: 0.163

GnomAD2 exomes AF: 0.0978 AC: 24453 AN: 250010 AF XY: 0.101

Gnomad AFR exome AF: 0.130

Gnomad AMR exome AF: 0.0556

Gnomad ASJ exome AF: 0.119

Gnomad EAS exome AF: 0.0413

Gnomad FIN exome AF: 0.0784

Gnomad NFE exome AF: 0.107

Gnomad OTH exome AF: 0.102

GnomAD4 exome AF: 0.123 AC: 167836 AN: 1362158 Hom.: 27562 Cov.: 47 AF XY: 0.124 AC XY: 84417 AN XY: 679452

African (AFR) AF: 0.145 AC: 4427 AN: 30436

American (AMR) AF: 0.0650 AC: 2775 AN: 42670

Ashkenazi Jewish (ASJ) AF: 0.137 AC: 3396 AN: 24722

East Asian (EAS) AF: 0.0351 AC: 1306 AN: 37224

South Asian (SAS) AF: 0.151 AC: 12601 AN: 83674

European-Finnish (FIN) AF: 0.0960 AC: 4721 AN: 49188

Middle Eastern (MID) AF: 0.184 AC: 867 AN: 4712

European-Non Finnish (NFE) AF: 0.126 AC: 130496 AN: 1033876

Other (OTH) AF: 0.130 AC: 7247 AN: 55656

GnomAD4 genome AF: 0.168 AC: 16501 AN: 98506 Hom.: 3367 Cov.: 15 AF XY: 0.170 AC XY: 8076 AN XY: 47472

African (AFR) AF: 0.225 AC: 5273 AN: 23438

American (AMR) AF: 0.135 AC: 1206 AN: 8938

Ashkenazi Jewish (ASJ) AF: 0.161 AC: 383 AN: 2378

East Asian (EAS) AF: 0.0750 AC: 247 AN: 3294

South Asian (SAS) AF: 0.169 AC: 524 AN: 3092

European-Finnish (FIN) AF: 0.134 AC: 860 AN: 6422

Middle Eastern (MID) AF: 0.223 AC: 41 AN: 184

European-Non Finnish (NFE) AF: 0.155 AC: 7577 AN: 48820

Other (OTH) AF: 0.160 AC: 204 AN: 1276

Alfa AF: 0.114 Hom.: 457

Asia WGS AF: 0.110 AC: 383 AN: 3478

EpiCase AF: 0.115

EpiControl AF: 0.110

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	12
DANN	Benign	0.75
PhyloP100		-0.82
PromoterAI		-0.071	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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: rs1050414; hg19: chr6-31239506; COSMIC: COSV66116499; COSMIC: COSV66116499;