NM_002117.6:c.89G>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_002117.6(HLA-C):c.89G>A(p.Arg30Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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 0.0070 ( 13 hom., cov: 12)

Exomes 𝑓: 0.030 ( 4025 hom. )

Failed GnomAD Quality Control

Consequence

HLA-C
NM_002117.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.481

Publications

13 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 -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.002752006).

BS2

High Homozygotes in GnomAd4 at 13 gene

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.89G>A	p.Arg30Lys	missense	Exon 2 of 8	NP_002108.4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
HLA-C	ENST00000376228.10	TSL:6 MANE Select	c.89G>A	p.Arg30Lys	missense	Exon 2 of 8	ENSP00000365402.5
HLA-C	ENST00000383329.7	TSL:6	c.89G>A	p.Arg30Lys	missense	Exon 2 of 8	ENSP00000372819.3
HLA-C	ENST00000956155.1		c.89G>A	p.Arg30Lys	missense	Exon 2 of 8	ENSP00000626214.1

Frequencies

GnomAD3 genomes

AF:

0.00706

AC:

598

AN:

84706

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00116

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00813

Gnomad ASJ

AF:

0.00858

Gnomad EAS

AF:

0.0338

Gnomad SAS

AF:

0.00650

Gnomad FIN

AF:

0.0107

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00820

Gnomad OTH

AF:

0.00668

GnomAD2 exomes

AF:

0.0478

AC:

11333

AN:

237132

AF XY:

0.0460

show subpopulations

Gnomad AFR exome

AF:

0.00672

Gnomad AMR exome

AF:

0.0632

Gnomad ASJ exome

AF:

0.0247

Gnomad EAS exome

AF:

0.173

Gnomad FIN exome

AF:

0.0607

Gnomad NFE exome

AF:

0.0320

Gnomad OTH exome

AF:

0.0461

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0301

AC:

35027

AN:

1162208

Hom.:

4025

Cov.:

AF XY:

0.0302

AC XY:

17547

AN XY:

581188

show subpopulations

African (AFR)

AF:

0.00547

AC:

134

AN:

24490

American (AMR)

AF:

0.0640

AC:

2282

AN:

35662

Ashkenazi Jewish (ASJ)

AF:

0.0246

AC:

507

AN:

20586

East Asian (EAS)

AF:

0.177

AC:

4544

AN:

25684

South Asian (SAS)

AF:

0.0304

AC:

2322

AN:

76446

European-Finnish (FIN)

AF:

0.0471

AC:

1709

AN:

36288

Middle Eastern (MID)

AF:

0.0176

AC:

AN:

3752

European-Non Finnish (NFE)

AF:

0.0249

AC:

22178

AN:

892148

Other (OTH)

AF:

0.0273

AC:

1285

AN:

47152

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.565

Heterozygous variant carriers

884

1768

2653

3537

4421

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

792

1584

2376

3168

3960

<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:

0.00704

AC:

597

AN:

84762

Hom.:

Cov.:

AF XY:

0.00719

AC XY:

292

AN XY:

40630

show subpopulations

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

African (AFR)

AF:

0.00116

AC:

AN:

20690

American (AMR)

AF:

0.00814

AC:

AN:

7374

Ashkenazi Jewish (ASJ)

AF:

0.00858

AC:

AN:

1632

East Asian (EAS)

AF:

0.0334

AC:

AN:

1858

South Asian (SAS)

AF:

0.00648

AC:

AN:

2470

European-Finnish (FIN)

AF:

0.0107

AC:

AN:

5434

Middle Eastern (MID)

AF:

0.00

AC:

AN:

174

European-Non Finnish (NFE)

AF:

0.00820

AC:

356

AN:

43406

Other (OTH)

AF:

0.00668

AC:

AN:

1048

⚠️ 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.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.310

Heterozygous variant carriers

104

155

207

259

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.0288

Hom.:

ExAC

AF:

0.0468

AC:

5611

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.44

CADD

Benign

(source)

DANN

Benign

0.91

DEOGEN2

Benign

0.039

Eigen

Benign

-0.73

Eigen_PC

Benign

-0.84

FATHMM_MKL

Benign

0.0065

LIST_S2

Benign

0.31

MetaRNN

Benign

0.0028

MetaSVM

Benign

-0.96

PhyloP100

0.48

PrimateAI

Benign

0.33

PROVEAN

Benign

-1.7

REVEL

Benign

0.14

Sift

Benign

0.053

Sift4G

Uncertain

0.042

Polyphen

0.0

Vest4

0.14

MPC

0.50

ClinPred

0.0041

GERP RS

1.4

PromoterAI

-0.034

Neutral

(source)

gMVP

0.40

Mutation Taster

=99/1

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.

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