6-31272119-T-C

Variant names:

• chr6-31272119-T-C
• rs2074491
• ENST00000495835.1:n.12A>G

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The ENST00000692808.2(ENSG00000288813):​n.724T>C 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: ENSG00000288813 ENST00000692808.2 non_coding_transcript_exon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.622
• Publications: 17 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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BS2: High Homozygotes in GnomAd4 at 446 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000692808.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HLA-C	NM_002117.6	MANE Select	c.-48A>G		upstream_gene	N/A	NP_002108.4	P10321-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HLA-C	ENST00000495835.1	TSL:6	n.12A>G		non_coding_transcript_exon	Exon 1 of 3
	ENSG00000288813	ENST00000692808.2		n.724T>C		non_coding_transcript_exon	Exon 1 of 1
	ENSG00000298396	ENST00000755297.1		n.32+1013T>C		intron	N/A

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

GnomAD2 exomes AF: 0.160 AC: 34481 AN: 215454 AF XY: 0.154

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 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

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0498 AC: 687 AN: 13790

American (AMR) AF: 0.0519 AC: 968 AN: 18658

Ashkenazi Jewish (ASJ) AF: 0.0259 AC: 302 AN: 11660

East Asian (EAS) AF: 0.101 AC: 1774 AN: 17636

South Asian (SAS) AF: 0.0326 AC: 1648 AN: 50540

European-Finnish (FIN) AF: 0.0379 AC: 914 AN: 24132

Middle Eastern (MID) AF: 0.0357 AC: 88 AN: 2468

European-Non Finnish (NFE) AF: 0.0188 AC: 9858 AN: 525670

Other (OTH) AF: 0.0290 AC: 884 AN: 30502

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

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

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0879 AC: 2332 AN: 26516

American (AMR) AF: 0.0649 AC: 636 AN: 9796

Ashkenazi Jewish (ASJ) AF: 0.0434 AC: 120 AN: 2764

East Asian (EAS) AF: 0.125 AC: 398 AN: 3186

South Asian (SAS) AF: 0.0324 AC: 104 AN: 3210

European-Finnish (FIN) AF: 0.0820 AC: 544 AN: 6636

Middle Eastern (MID) AF: 0.0508 AC: 13 AN: 256

European-Non Finnish (NFE) AF: 0.0654 AC: 3371 AN: 51578

Other (OTH) AF: 0.0683 AC: 97 AN: 1420

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.134 Hom.: 611

Asia WGS AF: 0.158 AC: 550 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	12
DANN	Benign	0.44
PhyloP100		-0.62
PromoterAI		-0.15	Neutral

Splicing

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

Other links and lift over

dbSNP: rs2074491; hg19: chr6-31239896;