Genetic Variant NM_002117.6:c.89G>A (chr6-31271853-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

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. 13/18 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

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

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4

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

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00704 (597/84762) while in subpopulation EAS AF= 0.0334 (62/1858). AF 95% confidence interval is 0.0267. There are 13 homozygotes in gnomad4. There are 292 alleles in male gnomad4 subpopulation. Median coverage is 12. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 13 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HLA-C	NM_002117.6 link	c.89G>A	p.Arg30Lys	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.89G>A	p.Arg30Lys	missense_variant	Exon 2 of 8	6	NM_002117.6	ENSP00000365402.5		P10321-1

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

GnomAD3 exomes

AF:

0.0478

AC:

11333

AN:

237132

Hom.:

441

AF XY:

0.0460

AC XY:

5950

AN XY:

129482

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 SAS exome

AF:

0.0328

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

Gnomad4 AFR exome

AF:

0.00547

Gnomad4 AMR exome

AF:

0.0640

Gnomad4 ASJ exome

AF:

0.0246

Gnomad4 EAS exome

AF:

0.177

Gnomad4 SAS exome

AF:

0.0304

Gnomad4 FIN exome

AF:

0.0471

Gnomad4 NFE exome

AF:

0.0249

Gnomad4 OTH exome

AF:

0.0273

GnomAD4 genome

AF:

0.00704

AC:

597

AN:

84762

Hom.:

Cov.:

AF XY:

0.00719

AC XY:

292

AN XY:

40630

show subpopulations

Gnomad4 AFR

AF:

0.00116

Gnomad4 AMR

AF:

0.00814

Gnomad4 ASJ

AF:

0.00858

Gnomad4 EAS

AF:

0.0334

Gnomad4 SAS

AF:

0.00648

Gnomad4 FIN

AF:

0.0107

Gnomad4 NFE

AF:

0.00820

Gnomad4 OTH

AF:

0.00668

Alfa

AF:

0.0288

Hom.:

ExAC

AF:

0.0468

AC:

5611

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.44

CADD

Benign

DANN

Benign

0.91

DEOGEN2

Benign

0.039

T;.

Eigen

Benign

-0.73

Eigen_PC

Benign

-0.84

FATHMM_MKL

Benign

0.0065

LIST_S2

Benign

0.31

T;T

MetaRNN

Benign

0.0028

T;T

MetaSVM

Benign

-0.96

PrimateAI

Benign

0.33

PROVEAN

Benign

-1.7

N;N

REVEL

Benign

0.14

Sift

Benign

0.053

T;T

Sift4G

Uncertain

0.042

D;D

Polyphen

0.0

B;B

Vest4

0.14

MPC

0.50

ClinPred

0.0041

GERP RS

1.4

gMVP

0.40

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over