ENST00000692808.2:n.869C>T

Variant names:

• chr6-31272264-C-T
• rs2524094
• ENST00000692808.2:n.869C>T

Variant summary

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

The ENST00000692808.2(ENSG00000288813):​n.869C>T variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.512 in 398,996 control chromosomes in the GnomAD database, including 57,148 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 0.56 (21454 hom., cov: 20)
  • Exomes 𝑓: 0.49 (35694 hom.)
• Consequence: ENSG00000288813 ENST00000692808.2 non_coding_transcript_exon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.219
• Publications: 28 publications found

Genes affected

ENSG00000288813 (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

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BS2: High Homozygotes in GnomAd4 at 21454 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HLA-C	NM_002117.6	MANE Select	c.-193G>A		upstream_gene	N/A	NP_002108.4

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ENSG00000288813	ENST00000692808.2		n.869C>T		non_coding_transcript_exon	Exon 1 of 1
	ENSG00000298396	ENST00000755297.1		n.32+1158C>T		intron	N/A
	HLA-C	ENST00000376228.10	TSL:6 MANE Select	c.-193G>A		upstream_gene	N/A	ENSP00000365402.5

Frequencies

GnomAD3 genomes AF: 0.556 AC: 75687 AN: 136236 Hom.: 21451 Cov.: 20

Gnomad AFR AF: 0.501

Gnomad AMI AF: 0.507

Gnomad AMR AF: 0.563

Gnomad ASJ AF: 0.655

Gnomad EAS AF: 0.744

Gnomad SAS AF: 0.613

Gnomad FIN AF: 0.506

Gnomad MID AF: 0.567

Gnomad NFE AF: 0.570

Gnomad OTH AF: 0.554

GnomAD4 exome AF: 0.489 AC: 128496 AN: 262654 Hom.: 35694 AF XY: 0.492 AC XY: 67608 AN XY: 137502

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

African (AFR) AF: 0.405 AC: 3083 AN: 7612

American (AMR) AF: 0.481 AC: 5230 AN: 10880

Ashkenazi Jewish (ASJ) AF: 0.569 AC: 4460 AN: 7834

East Asian (EAS) AF: 0.726 AC: 10464 AN: 14416

South Asian (SAS) AF: 0.580 AC: 19477 AN: 33560

European-Finnish (FIN) AF: 0.389 AC: 5109 AN: 13122

Middle Eastern (MID) AF: 0.508 AC: 580 AN: 1142

European-Non Finnish (NFE) AF: 0.458 AC: 72700 AN: 158814

Other (OTH) AF: 0.484 AC: 7393 AN: 15274

⚠️ 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: 0.555 AC: 75717 AN: 136342 Hom.: 21454 Cov.: 20 AF XY: 0.554 AC XY: 36432 AN XY: 65782

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

African (AFR) AF: 0.500 AC: 18091 AN: 36150

American (AMR) AF: 0.563 AC: 7564 AN: 13434

Ashkenazi Jewish (ASJ) AF: 0.655 AC: 2160 AN: 3298

East Asian (EAS) AF: 0.745 AC: 3331 AN: 4474

South Asian (SAS) AF: 0.611 AC: 2580 AN: 4222

European-Finnish (FIN) AF: 0.506 AC: 4450 AN: 8786

Middle Eastern (MID) AF: 0.561 AC: 156 AN: 278

European-Non Finnish (NFE) AF: 0.570 AC: 35913 AN: 62968

Other (OTH) AF: 0.553 AC: 1036 AN: 1872

⚠️ 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: 0.589 Hom.: 20638

Asia WGS AF: 0.638 AC: 2220 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	11
DANN	Benign	0.90
PhyloP100		-0.22
PromoterAI		-0.038	Neutral
Mutation Taster		=100/0	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs2524094; hg19: chr6-31240041; COSMIC: COSV66119511;