6-31271640-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

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. 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 same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.16 (1838 hom., cov: 9)
  • Exomes 𝑓: 0.19 (58049 hom.)
• Consequence: HLA-C NM_002117.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -4.50

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 -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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HLA-C	NM_002117.6	c.302G>A	p.Ser101Asn	missense_variant	2/8	ENST00000376228.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HLA-C	ENST00000376228.10	c.302G>A	p.Ser101Asn	missense_variant	2/8		NM_002117.6	P4

Frequencies

GnomAD3 genomes AF: 0.163 AC: 10087 AN: 61998 Hom.: 1835 Cov.: 9

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

GnomAD3 exomes AF: 0.373 AC: 93551 AN: 250578 Hom.: 18426 AF XY: 0.379 AC XY: 51388 AN XY: 135598

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 SAS exome AF: 0.438

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.: 32 AF XY: 0.199 AC XY: 98137 AN XY: 492494

Gnomad4 AFR exome AF: 0.392

Gnomad4 AMR exome AF: 0.232

Gnomad4 ASJ exome AF: 0.300

Gnomad4 EAS exome AF: 0.0722

Gnomad4 SAS exome AF: 0.301

Gnomad4 FIN exome AF: 0.219

Gnomad4 NFE exome AF: 0.176

Gnomad4 OTH exome AF: 0.215

GnomAD4 genome AF: 0.163 AC: 10098 AN: 62060 Hom.: 1838 Cov.: 9 AF XY: 0.158 AC XY: 4677 AN XY: 29558

Gnomad4 AFR AF: 0.271

Gnomad4 AMR AF: 0.117

Gnomad4 ASJ AF: 0.228

Gnomad4 EAS AF: 0.0566

Gnomad4 SAS AF: 0.133

Gnomad4 FIN AF: 0.0858

Gnomad4 NFE AF: 0.143

Gnomad4 OTH AF: 0.186

Alfa AF: 0.372 Hom.: 10082

TwinsUK AF: 0.337 AC: 1251

ALSPAC AF: 0.352 AC: 1355

ESP6500AA AF: 0.536 AC: 1619

ESP6500EA AF: 0.377 AC: 2041

ExAC AF: 0.378 AC: 45860

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 v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.60
Cadd	Benign	0.0070
Dann	Benign	0.87
DEOGEN2	Benign	0.022	T;.
Eigen	Benign	-1.9
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.0011	N
LIST_S2	Benign	0.010	T;T
MetaRNN	Benign	0.0056	T;T
MetaSVM	Benign	-0.94	T
MutationTaster	Benign	1.0	P;P;P;P
PrimateAI	Benign	0.27	T
PROVEAN	Benign	1.1	N;N
REVEL	Benign	0.12
Sift	Benign	0.73	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0	B;B
Vest4		0.071
MPC		0.46
ClinPred		0.0043	T
GERP RS		-4.1
gMVP		0.25

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: rs2308557; hg19: chr6-31239417; COSMIC: COSV66115617; COSMIC: COSV66115617;