Genetic Variant HLA-C:c.620-56C>G (chr6-31270541-G-C) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_002117.6(HLA-C):c.620-56C>G variant causes a intron 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 0.0 ( 0 hom., cov: 2)

Exomes 𝑓: 0.0000043 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

HLA-C
NM_002117.6 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.25

Publications

27 publications found

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.93).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HLA-C	NM_002117.6	MANE Select	c.620-56C>G		intron	N/A	NP_002108.4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
HLA-C	ENST00000376228.10	TSL:6 MANE Select	c.620-56C>G	intron	N/A	ENSP00000365402.5
HLA-C	ENST00000383329.7	TSL:6	c.620-56C>G	intron	N/A	ENSP00000372819.3
HLA-C	ENST00000415537.1	TSL:6	c.617-56C>G	intron	N/A	ENSP00000400410.1

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

56076

Hom.:

Cov.:

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000428

AC:

AN:

700142

Hom.:

Cov.:

AF XY:

0.00000578

AC XY:

AN XY:

345760

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

11546

American (AMR)

AF:

0.00

AC:

AN:

17288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

6020

East Asian (EAS)

AF:

0.0000906

AC:

AN:

11040

South Asian (SAS)

AF:

0.00

AC:

AN:

33294

European-Finnish (FIN)

AF:

0.00

AC:

AN:

25432

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1870

European-Non Finnish (NFE)

AF:

0.00000177

AC:

AN:

565896

Other (OTH)

AF:

0.0000360

AC:

AN:

27756

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.408

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

56076

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

26620

African (AFR)

AF:

0.00

AC:

AN:

10906

American (AMR)

AF:

0.00

AC:

AN:

4944

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

750

East Asian (EAS)

AF:

0.00

AC:

AN:

1412

South Asian (SAS)

AF:

0.00

AC:

AN:

1516

European-Finnish (FIN)

AF:

0.00

AC:

AN:

4040

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

31314

Other (OTH)

AF:

0.00

AC:

AN:

658

Alfa

AF:

0.00

Hom.:

1224

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.93

CADD

Benign

3.9

(source)

DANN

Benign

0.51

PhyloP100

-1.3

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over