6-31271724-G-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_002117.6(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
NM_002117.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.366

Publications

22 publications found

Variant links:

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]

HLA-C links:

ENSG00000288813 (HGNC:):

ENSG00000288813 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HLA-C	NM_002117.6 link	c.218C>A	p.Ala73Glu	missense_variant	Exon 2 of 8	ENST00000376228.10	NP_002108.4	P10321-1Q6R739Q95HC2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HLA-C	ENST00000376228.10 link	c.218C>A	p.Ala73Glu	missense_variant	Exon 2 of 8	6	NM_002117.6	ENSP00000365402.5		P10321-1

Frequencies

GnomAD3 genomes

AF:

0.0346

AC:

3209

AN:

92844

Hom.:

107

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.0656

AC XY:

42431

AN XY:

646730

show subpopulations

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.445

Heterozygous variant carriers

3086

6173

9259

12346

15432

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0346

AC:

3216

AN:

92904

Hom.:

107

Cov.:

AF XY:

0.0345

AC XY:

1547

AN XY:

44810

show subpopulations

⚠️ 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:

AN:

3344

South Asian (SAS)

AF:

0.0226

AC:

AN:

3010

European-Finnish (FIN)

AF:

0.0365

AC:

212

AN:

5810

Middle Eastern (MID)

AF:

0.0595

AC:

AN:

168

European-Non Finnish (NFE)

AF:

0.0279

AC:

1309

AN:

46900

Other (OTH)

AF:

0.0407

AC:

AN:

1180

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.325

Heterozygous variant carriers

220

441

661

882

1102

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

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 v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.29

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.39

CADD

Benign

(source)

DANN

Benign

0.93

DEOGEN2

Benign

0.021

T;.

Eigen

Benign

-0.31

Eigen_PC

Benign

-0.46

FATHMM_MKL

Benign

0.036

LIST_S2

Benign

0.39

T;T

MetaRNN

Benign

0.0017

T;T

MetaSVM

Benign

-1.1

PhyloP100

0.37

PrimateAI

Uncertain

0.53

PROVEAN

Uncertain

-3.4

D;D

REVEL

Benign

0.15

Sift

Benign

0.043

D;D

Sift4G

Uncertain

0.023

D;D

Polyphen

0.022

B;B

Vest4

0.10

MPC

0.61

ClinPred

0.10

GERP RS

1.9

PromoterAI

-0.026

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

gMVP

0.59

Mutation Taster

=95/5

polymorphism (auto)

(source)

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

6-31271724-G-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over