6-31272002-C-T

Variant names:

• chr6-31272002-C-T
• rs41553415
• NM_002117.6:c.70G>A

Variant summary

Our verdict is Benign. The variant received -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. 14/20 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
• Publications: 5 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]

ENSG00000288813 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 2656389.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAdExome4 at 17 gene

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.70G>A	p.Ala24Thr	missense	Exon 1 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.70G>A	p.Ala24Thr	missense	Exon 1 of 8	ENSP00000365402.5	P10321-1
	HLA-C	ENST00000383329.7	TSL:6	c.70G>A	p.Ala24Thr	missense	Exon 1 of 8	ENSP00000372819.3	A2AEA2
	HLA-C	ENST00000956155.1		c.70G>A	p.Ala24Thr	missense	Exon 1 of 8	ENSP00000626214.1

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

GnomAD2 exomes AF: 0.00219 AC: 535 AN: 244706 AF XY: 0.00218

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 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

African (AFR) AF: 0.00106 AC: 21 AN: 19786

American (AMR) AF: 0.00162 AC: 44 AN: 27228

Ashkenazi Jewish (ASJ) AF: 0.0115 AC: 183 AN: 15892

East Asian (EAS) AF: 0.00 AC: 0 AN: 25590

South Asian (SAS) AF: 0.00104 AC: 66 AN: 63638

European-Finnish (FIN) AF: 0.000804 AC: 26 AN: 32324

Middle Eastern (MID) AF: 0.00594 AC: 18 AN: 3028

European-Non Finnish (NFE) AF: 0.00107 AC: 803 AN: 750578

Other (OTH) AF: 0.00191 AC: 79 AN: 41374

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

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000875 AC: 18 AN: 20568

American (AMR) AF: 0.00153 AC: 12 AN: 7866

Ashkenazi Jewish (ASJ) AF: 0.00921 AC: 16 AN: 1738

East Asian (EAS) AF: 0.00 AC: 0 AN: 2466

South Asian (SAS) AF: 0.000801 AC: 2 AN: 2498

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5922

Middle Eastern (MID) AF: 0.00481 AC: 1 AN: 208

European-Non Finnish (NFE) AF: 0.00174 AC: 77 AN: 44276

Other (OTH) AF: 0.00177 AC: 2 AN: 1132

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000000000720202), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00428 Hom.: 1

ExAC AF: 0.00294 AC: 355

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Benign	0.0075	T
MetaRNN	Benign	0.0058	T
MetaSVM	Benign	-0.94	T
PhyloP100		0.11
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.12
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0070	D
Polyphen		1.0	D
Vest4		0.30
MVP		0.21
MPC		0.50
ClinPred		0.095	T
GERP RS		3.2
PromoterAI		-0.11	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
gMVP		0.18
Mutation Taster		=100/0	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: rs41553415; hg19: chr6-31239779;