6-31271640-C-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.302G>A(p.Ser101Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.191 in 1,044,290 control chromosomes in the GnomAD database, including 59,887 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 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 0.16 ( 1838 hom., cov: 9)

Exomes 𝑓: 0.19 ( 58049 hom. )

Consequence

HLA-C
NM_002117.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -4.50

Publications

30 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

new If you want to explore the variant's impact on the transcript NM_002117.6, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.005584508).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.263 is higher than 0.05.

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.302G>A	p.Ser101Asn	missense	Exon 2 of 8	NP_002108.4	P10321-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HLA-C	ENST00000376228.10	TSL:6 MANE Select	c.302G>A	p.Ser101Asn	missense	Exon 2 of 8	ENSP00000365402.5	P10321-1
HLA-C	ENST00000383329.7	TSL:6	c.302G>A	p.Ser101Asn	missense	Exon 2 of 8	ENSP00000372819.3	A2AEA2
HLA-C	ENST00000956155.1		c.302G>A	p.Ser101Asn	missense	Exon 2 of 8	ENSP00000626214.1

Frequencies

GnomAD3 genomes

AF:

0.163

AC:

10087

AN:

61998

Hom.:

1835

Cov.:

show subpopulations

Gnomad AFR

AF:

0.271

Gnomad AMI

AF:

0.314

Gnomad AMR

AF:

0.117

Gnomad ASJ

AF:

0.228

Gnomad EAS

AF:

0.0563

Gnomad SAS

AF:

0.135

Gnomad FIN

AF:

0.0858

Gnomad MID

AF:

0.237

Gnomad NFE

AF:

0.143

Gnomad OTH

AF:

0.189

GnomAD2 exomes

AF:

0.373

AC:

93551

AN:

250578

AF XY:

0.379

show subpopulations

Gnomad AFR exome

AF:

0.528

Gnomad AMR exome

AF:

0.360

Gnomad ASJ exome

AF:

0.423

Gnomad EAS exome

AF:

0.145

Gnomad FIN exome

AF:

0.368

Gnomad NFE exome

AF:

0.371

Gnomad OTH exome

AF:

0.388

GnomAD4 exome

AF:

0.193

AC:

189844

AN:

982230

Hom.:

58049

Cov.:

AF XY:

0.199

AC XY:

98137

AN XY:

492494

show subpopulations

African (AFR)

AF:

0.392

AC:

7443

AN:

18970

American (AMR)

AF:

0.232

AC:

6655

AN:

28676

Ashkenazi Jewish (ASJ)

AF:

0.300

AC:

5440

AN:

18120

East Asian (EAS)

AF:

0.0722

AC:

2030

AN:

28110

South Asian (SAS)

AF:

0.301

AC:

19408

AN:

64556

European-Finnish (FIN)

AF:

0.219

AC:

7668

AN:

35038

Middle Eastern (MID)

AF:

0.330

AC:

1080

AN:

3276

European-Non Finnish (NFE)

AF:

0.176

AC:

131324

AN:

744570

Other (OTH)

AF:

0.215

AC:

8796

AN:

40914

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.443

Heterozygous variant carriers

3425

6851

10276

13702

17127

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2800

5600

8400

11200

14000

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.163

AC:

10098

AN:

62060

Hom.:

1838

Cov.:

AF XY:

0.158

AC XY:

4677

AN XY:

29558

show subpopulations

African (AFR)

AF:

0.271

AC:

3246

AN:

11982

American (AMR)

AF:

0.117

AC:

645

AN:

5508

Ashkenazi Jewish (ASJ)

AF:

0.228

AC:

380

AN:

1670

East Asian (EAS)

AF:

0.0566

AC:

116

AN:

2050

South Asian (SAS)

AF:

0.133

AC:

256

AN:

1926

European-Finnish (FIN)

AF:

0.0858

AC:

330

AN:

3848

Middle Eastern (MID)

AF:

0.231

AC:

AN:

108

European-Non Finnish (NFE)

AF:

0.143

AC:

4828

AN:

33810

Other (OTH)

AF:

0.186

AC:

133

AN:

716

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.424

Heterozygous variant carriers

223

446

669

892

1115

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

104

208

312

416

520

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.387

Hom.:

16525

Asia WGS

AF:

0.347

AC:

1210

AN:

3478

EpiCase

AF:

0.388

EpiControl

AF:

0.396

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.68

BayesDel_noAF

Benign

-0.60

CADD

Benign

0.0070

(source)

DANN

Benign

0.87

DEOGEN2

Benign

0.022

Eigen

Benign

-1.9

Eigen_PC

Benign

-1.9

FATHMM_MKL

Benign

0.0011

LIST_S2

Benign

0.010

MetaRNN

Benign

0.0056

MetaSVM

Benign

-0.94

PhyloP100

-4.5

PrimateAI

Benign

0.27

PROVEAN

Benign

1.1

REVEL

Benign

0.12

Sift

Benign

0.73

Sift4G

Benign

1.0

PromoterAI

-0.058

Neutral

(source)

gMVP

0.25

Mutation Taster

=100/0

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

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over