rs1050384

Variant names:

• chr6-31271305-G-C
• rs1050384
• NM_002117.6:c.387C>G

Your query was ambiguous. Multiple possible variants found:

• chr6-31271305-G-C
• chr6-31271305-G-T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_Moderate BP7

The NM_002117.6(HLA-C):​c.387C>G​(p.Pro129Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0019 (1 hom., cov: 6)
  • Exomes 𝑓: 0.0073 (287 hom.)
  • Failed GnomAD Quality Control
• Consequence: HLA-C NM_002117.6 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -6.48
• Publications: 13 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]

ENSG00000298396 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.028).
• BP7: Synonymous conserved (PhyloP=-6.48 with no splicing effect.

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.387C>G	p.Pro129Pro	synonymous	Exon 3 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.387C>G	p.Pro129Pro	synonymous	Exon 3 of 8	ENSP00000365402.5	P10321-1
	HLA-C	ENST00000383329.7	TSL:6	c.387C>G	p.Pro129Pro	synonymous	Exon 3 of 8	ENSP00000372819.3	A2AEA2
	HLA-C	ENST00000956155.1		c.387C>G	p.Pro129Pro	synonymous	Exon 3 of 8	ENSP00000626214.1

Frequencies

GnomAD3 genomes AF: 0.00194 AC: 121 AN: 62276 Hom.: 1 Cov.: 6

Gnomad AFR AF: 0.00415

Gnomad AMI AF: 0.00655

Gnomad AMR AF: 0.00213

Gnomad ASJ AF: 0.00227

Gnomad EAS AF: 0.00665

Gnomad SAS AF: 0.00238

Gnomad FIN AF: 0.00163

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000734

Gnomad OTH AF: 0.00535

GnomAD2 exomes AF: 0.141 AC: 31387 AN: 222356 AF XY: 0.138

Gnomad AFR exome AF: 0.219

Gnomad AMR exome AF: 0.201

Gnomad ASJ exome AF: 0.231

Gnomad EAS exome AF: 0.0743

Gnomad FIN exome AF: 0.160

Gnomad NFE exome AF: 0.113

Gnomad OTH exome AF: 0.138

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00729 AC: 7209 AN: 988374 Hom.: 287 Cov.: 28 AF XY: 0.00795 AC XY: 3941 AN XY: 495880

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

African (AFR) AF: 0.0250 AC: 482 AN: 19316

American (AMR) AF: 0.0193 AC: 532 AN: 27576

Ashkenazi Jewish (ASJ) AF: 0.0276 AC: 391 AN: 14158

East Asian (EAS) AF: 0.0254 AC: 582 AN: 22876

South Asian (SAS) AF: 0.0285 AC: 1805 AN: 63224

European-Finnish (FIN) AF: 0.00371 AC: 117 AN: 31526

Middle Eastern (MID) AF: 0.0133 AC: 40 AN: 2998

European-Non Finnish (NFE) AF: 0.00360 AC: 2763 AN: 766762

Other (OTH) AF: 0.0124 AC: 497 AN: 39938

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00193 AC: 120 AN: 62308 Hom.: 1 Cov.: 6 AF XY: 0.00195 AC XY: 58 AN XY: 29720

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

African (AFR) AF: 0.00406 AC: 52 AN: 12818

American (AMR) AF: 0.00213 AC: 12 AN: 5628

Ashkenazi Jewish (ASJ) AF: 0.00227 AC: 2 AN: 882

East Asian (EAS) AF: 0.00670 AC: 11 AN: 1642

South Asian (SAS) AF: 0.00238 AC: 4 AN: 1684

European-Finnish (FIN) AF: 0.00163 AC: 7 AN: 4300

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 96

European-Non Finnish (NFE) AF: 0.000734 AC: 25 AN: 34044

Other (OTH) AF: 0.00529 AC: 4 AN: 756

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.130 Hom.: 28

Asia WGS AF: 0.186 AC: 648 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_noAF	Benign	-0.94
CADD	Benign	9.8
DANN	Benign	0.63
PhyloP100		-6.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1050384; hg19: chr6-31239082; COSMIC: COSV66112659; COSMIC: COSV66112659;