6-31271853-C-T

Position:

• chr6-31271853-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

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 same amino acid change has been previously reported as Likely benignin 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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.481

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 (HGNC:):

ACMG classification

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/exons	MANE	Protein	UniProt
HLA-C	NM_002117.6	c.89G>A	p.Arg30Lys	missense_variant	2/8	ENST00000376228.10	NP_002108.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HLA-C	ENST00000376228.10	c.89G>A	p.Arg30Lys	missense_variant	2/8	6	NM_002117.6	ENSP00000365402.5

Frequencies

GnomAD3 genomes AF: 0.00706 AC: 598 AN: 84706 Hom.: 13 Cov.: 12

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

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.: 36 AF XY: 0.0302 AC XY: 17547 AN XY: 581188

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.: 13 Cov.: 12 AF XY: 0.00719 AC XY: 292 AN XY: 40630

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.: 36

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	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	15
DANN	Benign	0.91
DEOGEN2	Benign	0.039	T;.
Eigen	Benign	-0.73
Eigen_PC	Benign	-0.84
FATHMM_MKL	Benign	0.0065	N
LIST_S2	Benign	0.31	T;T
MetaRNN	Benign	0.0028	T;T
MetaSVM	Benign	-0.96	T
PrimateAI	Benign	0.33	T
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	T
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

Other links and lift over

dbSNP: rs1131151; hg19: chr6-31239630; COSMIC: COSV66111479; COSMIC: COSV66111479;