rs2308592

Positions:

• chr6-31271153-A-C
• chr6-31271153-A-G
• chr6-31271153-A-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_002117.6(HLA-C):​c.539T>G​(p.Leu180Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 12/18 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 same amino acid change has been previously reported as Likely benignin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L180D) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0036 (3 hom., cov: 3)
  • Exomes 𝑓: 0.057 (9101 hom.)
  • Failed GnomAD Quality Control
• Consequence: HLA-C NM_002117.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -5.57

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]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0045161247).
• BS2: High Homozygotes in GnomAd4 at 3 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HLA-C	NM_002117.6	c.539T>G	p.Leu180Arg	missense_variant	3/8	ENST00000376228.10	NP_002108.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HLA-C	ENST00000376228.10	c.539T>G	p.Leu180Arg	missense_variant	3/8		NM_002117.6	ENSP00000365402	P4

Frequencies

GnomAD3 genomes AF: 0.00356 AC: 196 AN: 55054 Hom.: 3 Cov.: 3

Gnomad AFR AF: 0.00329

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00328

Gnomad ASJ AF: 0.00442

Gnomad EAS AF: 0.00982

Gnomad SAS AF: 0.00448

Gnomad FIN AF: 0.00235

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00350

Gnomad OTH AF: 0.00735

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0574 AC: 48545 AN: 845214 Hom.: 9101 Cov.: 29 AF XY: 0.0634 AC XY: 26800 AN XY: 422888

Gnomad4 AFR exome AF: 0.0655

Gnomad4 AMR exome AF: 0.107

Gnomad4 ASJ exome AF: 0.184

Gnomad4 EAS exome AF: 0.166

Gnomad4 SAS exome AF: 0.159

Gnomad4 FIN exome AF: 0.0602

Gnomad4 NFE exome AF: 0.0420

Gnomad4 OTH exome AF: 0.0617

GnomAD4 genome AF: 0.00358 AC: 197 AN: 55088 Hom.: 3 Cov.: 3 AF XY: 0.00369 AC XY: 97 AN XY: 26278

Gnomad4 AFR AF: 0.00328

Gnomad4 AMR AF: 0.00328

Gnomad4 ASJ AF: 0.00442

Gnomad4 EAS AF: 0.00988

Gnomad4 SAS AF: 0.00446

Gnomad4 FIN AF: 0.00235

Gnomad4 NFE AF: 0.00350

Gnomad4 OTH AF: 0.00875

ExAC AF: 0.329 AC: 38713

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	0.073
DANN	Benign	0.51
DEOGEN2	Benign	0.024	T;.;.
Eigen	Benign	-2.5
Eigen_PC	Benign	-2.6
FATHMM_MKL	Benign	0.0022	N
LIST_S2	Benign	0.0037	T;T;T
MetaRNN	Benign	0.0045	T;T;T
MetaSVM	Benign	-0.99	T
MutationTaster	Benign	1.0	P;P;P;P
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.39	N;N;.
REVEL	Uncertain	0.34
Sift	Benign	0.54	T;T;.
Sift4G	Benign	0.42	T;T;.
Polyphen		0.010	B;B;.
Vest4		0.075
MPC		0.74
ClinPred		0.0052	T
GERP RS		-5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.23

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

Other links and lift over

dbSNP: rs2308592; hg19: chr6-31238930; COSMIC: COSV66109994; COSMIC: COSV66109994;