6-31271153-A-G

Variant names:

• chr6-31271153-A-G
• rs2308592
• NM_002117.6:c.539T>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_002117.6(HLA-C):​c.539T>C​(p.Leu180Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 12/20 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. L180V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 3)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: HLA-C NM_002117.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -5.57
• Publications: 25 publications found

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]

ENSG00000298396 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.17858464).

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.539T>C	p.Leu180Pro	missense	Exon 3 of 8	NP_002108.4	P10321-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HLA-C	ENST00000376228.10	TSL:6 MANE Select	c.539T>C	p.Leu180Pro	missense	Exon 3 of 8	ENSP00000365402.5	P10321-1
	HLA-C	ENST00000383329.7	TSL:6	c.539T>C	p.Leu180Pro	missense	Exon 3 of 8	ENSP00000372819.3	A2AEA2
	HLA-C	ENST00000956155.1		c.539T>C	p.Leu180Pro	missense	Exon 3 of 8	ENSP00000626214.1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 56686 Hom.: 0 Cov.: 3

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 885012 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 443078

African (AFR) AF: 0.00 AC: 0 AN: 18528

American (AMR) AF: 0.00 AC: 0 AN: 27596

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 11244

East Asian (EAS) AF: 0.00 AC: 0 AN: 16656

South Asian (SAS) AF: 0.00 AC: 0 AN: 57594

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 25686

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2518

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 689418

Other (OTH) AF: 0.00 AC: 0 AN: 35772

GnomAD4 genome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 56686 Hom.: 0 Cov.: 3 AF XY: 0.00 AC XY: 0 AN XY: 26994

African (AFR) AF: 0.00 AC: 0 AN: 11790

American (AMR) AF: 0.00 AC: 0 AN: 5304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 712

East Asian (EAS) AF: 0.00 AC: 0 AN: 1400

South Asian (SAS) AF: 0.00 AC: 0 AN: 1616

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 3920

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 98

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 30744

Other (OTH) AF: 0.00 AC: 0 AN: 696

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Benign	-0.080	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	4.9
DANN	Benign	0.58
DEOGEN2	Benign	0.11	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.012	N
LIST_S2	Benign	0.0026	T
M_CAP	Benign	0.0011	T
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-0.85	T
PhyloP100		-5.6
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-1.6	N
REVEL	Uncertain	0.30
Sift	Benign	0.12	T
Sift4G	Benign	0.17	T
Polyphen		0.99	D
Vest4		0.27
MutPred		0.27		Loss of helix (P = 0.0093)
MVP		0.13
MPC		1.7
ClinPred		0.95	D
GERP RS		-5.6
gMVP		0.48
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs2308592; hg19: chr6-31238930;