Genetic Variant HLA-B:p.His212Gln (chr6-31355576-G-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_005514.8(HLA-B):c.636C>A(p.His212Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000172 in 1,163,410 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

Frequency

Genomes: not found (cov: 9)

Exomes 𝑓: 0.0000017 ( 0 hom. )

Consequence

HLA-B
NM_005514.8 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -2.26

Publications

0 publications found

Variant links:

Genes affected

HLA-B (HGNC:4932): (major histocompatibility complex, class I, B) HLA-B 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 the endoplasmic reticulum lumen. They are expressed in nearly all cells. The heavy chain is approximately 45 kDa and its gene contains 8 exons. Exon 1 encodes the leader peptide, exon 2 and 3 encode the alpha1 and alpha2 domains, 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. Hundreds of HLA-B alleles have been described. [provided by RefSeq, Jul 2008]

HLA-B links:

ENSG00000298396 (HGNC:):

ENSG00000298396 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.18020114).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005514.8. 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-B	NM_005514.8	MANE Select	c.636C>A	p.His212Gln	missense	Exon 4 of 8	NP_005505.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
HLA-B	ENST00000412585.7	TSL:6 MANE Select	c.636C>A	p.His212Gln	missense	Exon 4 of 8	ENSP00000399168.2
HLA-B	ENST00000696559.1		c.636C>A	p.His212Gln	missense	Exon 7 of 11	ENSP00000512717.1
HLA-B	ENST00000696560.1		c.636C>A	p.His212Gln	missense	Exon 6 of 10	ENSP00000512718.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000172

AC:

AN:

1163410

Hom.:

Cov.:

AF XY:

0.00000342

AC XY:

AN XY:

585474

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

27174

American (AMR)

AF:

0.00

AC:

AN:

39210

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22020

East Asian (EAS)

AF:

0.00

AC:

AN:

34884

South Asian (SAS)

AF:

0.0000126

AC:

AN:

79264

European-Finnish (FIN)

AF:

0.00

AC:

AN:

47380

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4352

European-Non Finnish (NFE)

AF:

0.00000116

AC:

AN:

860210

Other (OTH)

AF:

0.00

AC:

AN:

48916

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.400

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

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.45

CADD

Benign

(source)

DANN

Benign

0.56

DEOGEN2

Benign

0.037

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.8

FATHMM_MKL

Benign

0.0083

LIST_S2

Benign

0.30

M_CAP

Benign

0.0032

MetaRNN

Benign

0.18

MetaSVM

Benign

-0.99

PhyloP100

-2.3

PROVEAN

Pathogenic

-4.8

REVEL

Benign

0.18

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.054

Polyphen

1.0

Vest4

0.14

MutPred

0.59

Loss of sheet (P = 0.0817)

MVP

0.030

MPC

0.82

ClinPred

0.85

GERP RS

-6.4

PromoterAI

-0.015

Neutral

(source)

Varity_R

0.31

gMVP

0.067

Mutation Taster

=99/1

polymorphism

(source)

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