chr6-31270541-G-A

Variant names:

• chr6-31270541-G-A
• rs9264638
• NM_002117.6:c.620-56C>T

Variant summary

Our verdict is Likely benign. The variant received -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. 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
• Publications: 27 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]

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002117.6. 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.620-56C>T		intron	N/A	NP_002108.4	P10321-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HLA-C	ENST00000376228.10	TSL:6 MANE Select	c.620-56C>T		intron	N/A	ENSP00000365402.5	P10321-1
	HLA-C	ENST00000383329.7	TSL:6	c.620-56C>T		intron	N/A	ENSP00000372819.3	A2AEA2
	HLA-C	ENST00000956155.1		c.620-56C>T		intron	N/A	ENSP00000626214.1

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

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

African (AFR) AF: 0.00554 AC: 63 AN: 11372

American (AMR) AF: 0.00370 AC: 63 AN: 17026

Ashkenazi Jewish (ASJ) AF: 0.00438 AC: 26 AN: 5942

East Asian (EAS) AF: 0.00246 AC: 27 AN: 10976

South Asian (SAS) AF: 0.00999 AC: 328 AN: 32836

European-Finnish (FIN) AF: 0.00419 AC: 106 AN: 25278

Middle Eastern (MID) AF: 0.00597 AC: 11 AN: 1842

European-Non Finnish (NFE) AF: 0.000956 AC: 537 AN: 561866

Other (OTH) AF: 0.00207 AC: 57 AN: 27550

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

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

African (AFR) AF: 0.00243 AC: 26 AN: 10684

American (AMR) AF: 0.00268 AC: 13 AN: 4856

Ashkenazi Jewish (ASJ) AF: 0.00138 AC: 1 AN: 724

East Asian (EAS) AF: 0.000736 AC: 1 AN: 1358

South Asian (SAS) AF: 0.00201 AC: 3 AN: 1496

European-Finnish (FIN) AF: 0.000751 AC: 3 AN: 3996

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 94

European-Non Finnish (NFE) AF: 0.00108 AC: 33 AN: 30560

Other (OTH) AF: 0.00154 AC: 1 AN: 650

⚠️ 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: 0.152 Hom.: 1224

Asia WGS AF: 0.758 AC: 2637 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	4.3
DANN	Benign	0.62
PhyloP100		-1.3
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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs9264638;

hg19: chr6-31238318;

COSMIC: COSV66112539;

COSMIC: COSV66112539;