chr6-32664917-C-G

Variant names:

• chr6-32664917-C-G
• rs1130380
• NM_002123.5:c.260G>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002123.5(HLA-DQB1):​c.260G>C​(p.Arg87Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.35 (11130 hom., cov: 20)
  • Exomes 𝑓: 0.28 (55025 hom.)
  • Failed GnomAD Quality Control
• Consequence: HLA-DQB1 NM_002123.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.297
• Publications: 25 publications found

Genes affected

HLA-DQB1 (HGNC:4944): (major histocompatibility complex, class II, DQ beta 1) HLA-DQB1 belongs to the HLA class II beta chain paralogs. This class II molecule is a heterodimer consisting of an alpha (DQA) and a beta chain (DQB), both anchored in the membrane. It plays a central role in the immune system by presenting peptides derived from extracellular proteins. Class II molecules are expressed in antigen presenting cells (APC: B lymphocytes, dendritic cells, macrophages). The beta chain is approximately 26-28 kDa and it contains six exons. Exon 1 encodes the leader peptide, exons 2 and 3 encode the two extracellular domains, exon 4 encodes the transmembrane domain and exon 5 encodes the cytoplasmic tail. Within the DQ molecule both the alpha chain and the beta chain contain the polymorphisms specifying the peptide binding specificities, resulting in up to four different molecules. Typing for these polymorphisms is routinely done for bone marrow transplantation. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2011]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.6105175E-4).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.441 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HLA-DQB1	NM_002123.5	c.260G>C	p.Arg87Pro	missense_variant	Exon 2 of 5	ENST00000434651.7	NP_002114.3
HLA-DQB1	NM_001243961.2	c.260G>C	p.Arg87Pro	missense_variant	Exon 2 of 6		NP_001230890.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HLA-DQB1	ENST00000434651.7	c.260G>C	p.Arg87Pro	missense_variant	Exon 2 of 5	6	NM_002123.5	ENSP00000407332.2
HLA-DQB1	ENST00000374943.8	c.260G>C	p.Arg87Pro	missense_variant	Exon 2 of 6	6		ENSP00000364080.4

Frequencies

GnomAD3 genomes AF: 0.350 AC: 43512 AN: 124172 Hom.: 11128 Cov.: 20

Gnomad AFR AF: 0.255

Gnomad AMI AF: 0.468

Gnomad AMR AF: 0.442

Gnomad ASJ AF: 0.496

Gnomad EAS AF: 0.456

Gnomad SAS AF: 0.286

Gnomad FIN AF: 0.287

Gnomad MID AF: 0.457

Gnomad NFE AF: 0.381

Gnomad OTH AF: 0.370

GnomAD2 exomes AF: 0.338 AC: 52770 AN: 156124 AF XY: 0.335

Gnomad AFR exome AF: 0.142

Gnomad AMR exome AF: 0.548

Gnomad ASJ exome AF: 0.485

Gnomad EAS exome AF: 0.432

Gnomad FIN exome AF: 0.255

Gnomad NFE exome AF: 0.307

Gnomad OTH exome AF: 0.313

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.276 AC: 295407 AN: 1069964 Hom.: 55025 Cov.: 31 AF XY: 0.279 AC XY: 151372 AN XY: 541638

African (AFR) AF: 0.171 AC: 4470 AN: 26066

American (AMR) AF: 0.460 AC: 17673 AN: 38404

Ashkenazi Jewish (ASJ) AF: 0.427 AC: 9198 AN: 21560

East Asian (EAS) AF: 0.398 AC: 13985 AN: 35114

South Asian (SAS) AF: 0.262 AC: 19699 AN: 75162

European-Finnish (FIN) AF: 0.288 AC: 13899 AN: 48228

Middle Eastern (MID) AF: 0.356 AC: 1677 AN: 4706

European-Non Finnish (NFE) AF: 0.260 AC: 201115 AN: 774738

Other (OTH) AF: 0.298 AC: 13691 AN: 45986

GnomAD4 genome AF: 0.350 AC: 43542 AN: 124264 Hom.: 11130 Cov.: 20 AF XY: 0.347 AC XY: 21004 AN XY: 60598

African (AFR) AF: 0.255 AC: 8357 AN: 32768

American (AMR) AF: 0.443 AC: 5520 AN: 12472

Ashkenazi Jewish (ASJ) AF: 0.496 AC: 1509 AN: 3044

East Asian (EAS) AF: 0.457 AC: 2011 AN: 4396

South Asian (SAS) AF: 0.285 AC: 1025 AN: 3592

European-Finnish (FIN) AF: 0.287 AC: 2512 AN: 8762

Middle Eastern (MID) AF: 0.450 AC: 100 AN: 222

European-Non Finnish (NFE) AF: 0.381 AC: 21536 AN: 56580

Other (OTH) AF: 0.368 AC: 603 AN: 1640

Alfa AF: 0.168 Hom.: 384

ExAC AF: 0.366 AC: 43391

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	13
DANN	Benign	0.85
DEOGEN2	Benign	0.021	T;T;.;.
Eigen	Benign	-2.0
Eigen_PC	Benign	-2.0
FATHMM_MKL	Benign	0.032	N
LIST_S2	Benign	0.14	T;T;.;T
MetaRNN	Benign	0.00016	T;T;T;T
MetaSVM	Benign	-0.91	T
PhyloP100		0.30
PrimateAI	Benign	0.31	T
PROVEAN	Pathogenic	-5.9	D;D;D;D
REVEL	Benign	0.12
Sift	Benign	0.17	T;T;T;T
Sift4G	Uncertain	0.028	D;D;D;D
Polyphen		0.0030	B;.;B;B
Vest4		0.16
MPC		0.82
ClinPred		0.061	T
GERP RS		0.19
gMVP		0.55
Mutation Taster		=100/0	polymorphism (auto)

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: rs1130380; hg19: chr6-32632694; COSMIC: COSV66568910; COSMIC: COSV66568910;