6-31271724-G-T

Variant names:

• chr6-31271724-G-T
• rs1050409
• NM_002117.6:c.218C>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000376228.10(HLA-C):​c.218C>A​(p.Ala73Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0617 in 1,388,764 control chromosomes in the GnomAD database, including 9,180 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.035 (107 hom., cov: 14)
  • Exomes 𝑓: 0.064 (9073 hom.)
• Consequence: HLA-C ENST00000376228.10 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.366
• 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0017168224).
• BA1: GnomAdExome4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.155 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000376228.10. 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.218C>A	p.Ala73Glu	missense	Exon 2 of 8	NP_002108.4

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HLA-C	ENST00000376228.10	TSL:6 MANE Select	c.218C>A	p.Ala73Glu	missense	Exon 2 of 8	ENSP00000365402.5
	HLA-C	ENST00000383329.7	TSL:6	c.218C>A	p.Ala73Glu	missense	Exon 2 of 8	ENSP00000372819.3
	HLA-C	ENST00000415537.1	TSL:6	c.215C>A	p.Ala72Glu	missense	Exon 2 of 5	ENSP00000400410.1

Frequencies

GnomAD3 genomes AF: 0.0346 AC: 3209 AN: 92844 Hom.: 107 Cov.: 14

Gnomad AFR AF: 0.0486

Gnomad AMI AF: 0.0503

Gnomad AMR AF: 0.0358

Gnomad ASJ AF: 0.0719

Gnomad EAS AF: 0.0116

Gnomad SAS AF: 0.0226

Gnomad FIN AF: 0.0365

Gnomad MID AF: 0.0598

Gnomad NFE AF: 0.0279

Gnomad OTH AF: 0.0411

GnomAD2 exomes AF: 0.130 AC: 32609 AN: 250518 AF XY: 0.128

Gnomad AFR exome AF: 0.200

Gnomad AMR exome AF: 0.188

Gnomad ASJ exome AF: 0.197

Gnomad EAS exome AF: 0.0487

Gnomad FIN exome AF: 0.169

Gnomad NFE exome AF: 0.106

Gnomad OTH exome AF: 0.126

GnomAD4 exome AF: 0.0636 AC: 82475 AN: 1295860 Hom.: 9073 Cov.: 39 AF XY: 0.0656 AC XY: 42431 AN XY: 646730

African (AFR) AF: 0.159 AC: 4448 AN: 27968

American (AMR) AF: 0.153 AC: 6037 AN: 39340

Ashkenazi Jewish (ASJ) AF: 0.156 AC: 3580 AN: 22920

East Asian (EAS) AF: 0.0330 AC: 1203 AN: 36430

South Asian (SAS) AF: 0.0901 AC: 7041 AN: 78180

European-Finnish (FIN) AF: 0.127 AC: 5754 AN: 45290

Middle Eastern (MID) AF: 0.112 AC: 493 AN: 4392

European-Non Finnish (NFE) AF: 0.0509 AC: 50287 AN: 988632

Other (OTH) AF: 0.0689 AC: 3632 AN: 52708

GnomAD4 genome AF: 0.0346 AC: 3216 AN: 92904 Hom.: 107 Cov.: 14 AF XY: 0.0345 AC XY: 1547 AN XY: 44810

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

African (AFR) AF: 0.0487 AC: 1045 AN: 21448

American (AMR) AF: 0.0359 AC: 295 AN: 8218

Ashkenazi Jewish (ASJ) AF: 0.0719 AC: 159 AN: 2210

East Asian (EAS) AF: 0.0117 AC: 39 AN: 3344

South Asian (SAS) AF: 0.0226 AC: 68 AN: 3010

European-Finnish (FIN) AF: 0.0365 AC: 212 AN: 5810

Middle Eastern (MID) AF: 0.0595 AC: 10 AN: 168

European-Non Finnish (NFE) AF: 0.0279 AC: 1309 AN: 46900

Other (OTH) AF: 0.0407 AC: 48 AN: 1180

⚠️ 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: 0.108 Hom.: 460

TwinsUK AF: 0.0785 AC: 291

ALSPAC AF: 0.0838 AC: 323

ESP6500AA AF: 0.190 AC: 574

ESP6500EA AF: 0.113 AC: 610

ExAC AF: 0.129 AC: 15601

Asia WGS AF: 0.112 AC: 392 AN: 3476

EpiCase AF: 0.119

EpiControl AF: 0.128

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	19
DANN	Benign	0.93
DEOGEN2	Benign	0.021	T
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.46
FATHMM_MKL	Benign	0.036	N
LIST_S2	Benign	0.39	T
MetaRNN	Benign	0.0017	T
MetaSVM	Benign	-1.1	T
PhyloP100		0.37
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-3.4	D
REVEL	Benign	0.15
Sift	Benign	0.043	D
Sift4G	Uncertain	0.023	D
Polyphen		0.022	B
Vest4		0.10
MPC		0.61
ClinPred		0.10	T
GERP RS		1.9
PromoterAI		-0.026	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.59
Mutation Taster		=95/5	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: rs1050409; hg19: chr6-31239501; COSMIC: COSV66115644; COSMIC: COSV66115644;