6-31272002-C-T

Position:

• chr6-31272002-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_002117.6(HLA-C):​c.70G>A​(p.Ala24Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00128 in 1,066,756 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0015 (1 hom., cov: 12)
  • Exomes 𝑓: 0.0013 (17 hom.)
• Consequence: HLA-C NM_002117.6 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.109

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005843401).
• BP6: Variant 6-31272002-C-T is Benign according to our data. Variant chr6-31272002-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 2656389.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAdExome4 at 17 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HLA-C	NM_002117.6	c.70G>A	p.Ala24Thr	missense_variant	1/8	ENST00000376228.10	NP_002108.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HLA-C	ENST00000376228.10	c.70G>A	p.Ala24Thr	missense_variant	1/8		NM_002117.6	ENSP00000365402	P4

Frequencies

GnomAD3 genomes AF: 0.00147 AC: 128 AN: 87254 Hom.: 1 Cov.: 12

Gnomad AFR AF: 0.000879

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00153

Gnomad ASJ AF: 0.00921

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000802

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00435

Gnomad NFE AF: 0.00174

Gnomad OTH AF: 0.00178

GnomAD3 exomes AF: 0.00219 AC: 535 AN: 244706 Hom.: 6 AF XY: 0.00218 AC XY: 291 AN XY: 133402

Gnomad AFR exome AF: 0.00177

Gnomad AMR exome AF: 0.00166

Gnomad ASJ exome AF: 0.00985

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000920

Gnomad FIN exome AF: 0.00112

Gnomad NFE exome AF: 0.00264

Gnomad OTH exome AF: 0.00233

GnomAD4 exome AF: 0.00127 AC: 1240 AN: 979438 Hom.: 17 Cov.: 25 AF XY: 0.00129 AC XY: 630 AN XY: 489458

Gnomad4 AFR exome AF: 0.00106

Gnomad4 AMR exome AF: 0.00162

Gnomad4 ASJ exome AF: 0.0115

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00104

Gnomad4 FIN exome AF: 0.000804

Gnomad4 NFE exome AF: 0.00107

Gnomad4 OTH exome AF: 0.00191

GnomAD4 genome AF: 0.00147 AC: 128 AN: 87318 Hom.: 1 Cov.: 12 AF XY: 0.00137 AC XY: 57 AN XY: 41676

Gnomad4 AFR AF: 0.000875

Gnomad4 AMR AF: 0.00153

Gnomad4 ASJ AF: 0.00921

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000801

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00174

Gnomad4 OTH AF: 0.00177

Alfa AF: 0.00428 Hom.: 1

ExAC AF: 0.00294 AC: 355

Asia WGS AF: 0.00115 AC: 4 AN: 3478

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

Mar 01, 2024

HLA-C: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.029	T;.
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.43
FATHMM_MKL	Benign	0.047	N
LIST_S2	Benign	0.78	T;T
M_CAP	Benign	0.0075	T
MetaRNN	Benign	0.0058	T;T
MetaSVM	Benign	-0.94	T
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-1.8	N;N
REVEL	Benign	0.12
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.0070	D;D
Polyphen		1.0	D;D
Vest4		0.30
MVP		0.21
MPC		0.50
ClinPred		0.095	T
GERP RS		3.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
gMVP		0.18

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: rs41553415; hg19: chr6-31239779;