6-31272048-G-A

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_Strong BP6_Moderate BP7

The NM_002117.6(HLA-C):c.24C>T(p.Ala8=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 12)
  • Exomes 𝑓: 0.000071 (1 hom.)
  • Failed GnomAD Quality Control
• Consequence: HLA-C NM_002117.6 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.535

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 -7 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 6-31272048-G-A is Benign according to our data. Variant chr6-31272048-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 2656390.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.535 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HLA-C	NM_002117.6	c.24C>T	p.Ala8=	synonymous_variant	1/8	ENST00000376228.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HLA-C	ENST00000376228.10	c.24C>T	p.Ala8=	synonymous_variant	1/8		NM_002117.6	P4

Frequencies

GnomAD3 genomes AF: 0.00 AC: 13 AN: 92638 Hom.: 0 Cov.: 12 FAILED QC

Gnomad AFR AF: 0.0000909

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000357

Gnomad ASJ AF: 0.00104

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000108

Gnomad OTH AF: 0.000849

GnomAD3 exomes AF: 0.000495 AC: 122 AN: 246634 Hom.: 0 AF XY: 0.000485 AC XY: 65 AN XY: 134104

Gnomad AFR exome AF: 0.000858

Gnomad AMR exome AF: 0.000523

Gnomad ASJ exome AF: 0.00191

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.000557

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000406

Gnomad OTH exome AF: 0.00133

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000706 AC: 66 AN: 934776 Hom.: 1 Cov.: 23 AF XY: 0.0000813 AC XY: 38 AN XY: 467142

Gnomad4 AFR exome AF: 0.000214

Gnomad4 AMR exome AF: 0.000315

Gnomad4 ASJ exome AF: 0.000414

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000203

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000375

Gnomad4 OTH exome AF: 0.000178

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.000140 AC: 13 AN: 92700 Hom.: 0 Cov.: 12 AF XY: 0.000136 AC XY: 6 AN XY: 44172

Gnomad4 AFR AF: 0.0000905

Gnomad4 AMR AF: 0.000357

Gnomad4 ASJ AF: 0.00104

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000108

Gnomad4 OTH AF: 0.000840

Alfa AF: 0.000408 Hom.: 0

EpiCase AF: 0.000981

EpiControl AF: 0.000594

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jul 01, 2022

HLA-C: BP4, BP7 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
Cadd	Benign	9.1
Dann	Benign	0.80
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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: rs41543119; hg19: chr6-31239825;