rs10657191

Variant names:

• chr6-31272233-G-GAGA
• rs10657191
• ENST00000692808.2:n.841_843dupAAG

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The ENST00000692808.2(ENSG00000288813):​n.841_843dupAAG 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 0.416 in 226,596 control chromosomes in the GnomAD database, including 28,331 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.58 (20343 hom., cov: 0)
  • Exomes 𝑓: 0.42 (28331 hom.)
  • Failed GnomAD Quality Control
• Consequence: ENSG00000288813 ENST00000692808.2 non_coding_transcript_exon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.363
• Publications: 3 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: Likely_benign. The variant received -4 ACMG points.

• BS2: High Homozygotes in GnomAdExome4 at 28331 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HLA-C	NM_002117.6	c.-163_-162insTCT		upstream_gene_variant		ENST00000376228.10	NP_002108.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HLA-C	ENST00000376228.10	c.-165_-163dupTCT		upstream_gene_variant		6	NM_002117.6	ENSP00000365402.5

Frequencies

GnomAD3 genomes AF: 0.580 AC: 66109 AN: 113916 Hom.: 20325 Cov.: 0

Gnomad AFR AF: 0.660

Gnomad AMI AF: 0.510

Gnomad AMR AF: 0.601

Gnomad ASJ AF: 0.718

Gnomad EAS AF: 0.664

Gnomad SAS AF: 0.656

Gnomad FIN AF: 0.571

Gnomad MID AF: 0.744

Gnomad NFE AF: 0.515

Gnomad OTH AF: 0.622

GnomAD4 exome AF: 0.416 AC: 94197 AN: 226596 Hom.: 28331 AF XY: 0.427 AC XY: 50882 AN XY: 119112

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

African (AFR) AF: 0.523 AC: 3052 AN: 5834

American (AMR) AF: 0.518 AC: 4556 AN: 8790

Ashkenazi Jewish (ASJ) AF: 0.675 AC: 4088 AN: 6054

East Asian (EAS) AF: 0.599 AC: 6341 AN: 10584

South Asian (SAS) AF: 0.635 AC: 17143 AN: 26978

European-Finnish (FIN) AF: 0.323 AC: 3530 AN: 10942

Middle Eastern (MID) AF: 0.580 AC: 574 AN: 990

European-Non Finnish (NFE) AF: 0.345 AC: 49524 AN: 143664

Other (OTH) AF: 0.422 AC: 5389 AN: 12760

⚠️ 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 Data not reliable, filtered out with message: AS_VQSR AF: 0.580 AC: 66166 AN: 114016 Hom.: 20343 Cov.: 0 AF XY: 0.584 AC XY: 31581 AN XY: 54084

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

African (AFR) AF: 0.660 AC: 19768 AN: 29970

American (AMR) AF: 0.601 AC: 6312 AN: 10504

Ashkenazi Jewish (ASJ) AF: 0.718 AC: 2150 AN: 2994

East Asian (EAS) AF: 0.664 AC: 2393 AN: 3604

South Asian (SAS) AF: 0.654 AC: 2202 AN: 3368

European-Finnish (FIN) AF: 0.571 AC: 3664 AN: 6412

Middle Eastern (MID) AF: 0.733 AC: 173 AN: 236

European-Non Finnish (NFE) AF: 0.515 AC: 28167 AN: 54644

Other (OTH) AF: 0.624 AC: 944 AN: 1514

⚠️ 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: 0.570 Hom.: 2509

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.36
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs10657191; hg19: chr6-31240010;