NM_002123.5:c.295G>C

Variant names:

• chr6-32664882-C-G
• rs9274390
• NM_002123.5:c.295G>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_002123.5(HLA-DQB1):​c.295G>C​(p.Val99Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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.

• Frequency:
  • Genomes: 𝑓 0.0000084 (0 hom., cov: 20)
  • Exomes 𝑓: 0.000033 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: HLA-DQB1 NM_002123.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -13.4
• Publications: 26 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: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.13115796).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002123.5. 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-DQB1	NM_002123.5	MANE Select	c.295G>C	p.Val99Leu	missense	Exon 2 of 5	NP_002114.3
	HLA-DQB1	NM_001243961.2		c.295G>C	p.Val99Leu	missense	Exon 2 of 6	NP_001230890.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HLA-DQB1	ENST00000434651.7	TSL:6 MANE Select	c.295G>C	p.Val99Leu	missense	Exon 2 of 5	ENSP00000407332.2
	HLA-DQB1	ENST00000374943.8	TSL:6	c.295G>C	p.Val99Leu	missense	Exon 2 of 6	ENSP00000364080.4
	HLA-DQB1	ENST00000399084.5	TSL:6	c.295G>C	p.Val99Leu	missense	Exon 3 of 6	ENSP00000382034.1

Frequencies

GnomAD3 genomes AF: 0.00000843 AC: 1 AN: 118594 Hom.: 0 Cov.: 20

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: 0.0000183

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000326 AC: 35 AN: 1074676 Hom.: 0 Cov.: 28 AF XY: 0.0000257 AC XY: 14 AN XY: 545048

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

African (AFR) AF: 0.000120 AC: 3 AN: 25008

American (AMR) AF: 0.00 AC: 0 AN: 39464

Ashkenazi Jewish (ASJ) AF: 0.0000445 AC: 1 AN: 22448

East Asian (EAS) AF: 0.00 AC: 0 AN: 36156

South Asian (SAS) AF: 0.00 AC: 0 AN: 73882

European-Finnish (FIN) AF: 0.000128 AC: 6 AN: 46902

Middle Eastern (MID) AF: 0.000224 AC: 1 AN: 4468

European-Non Finnish (NFE) AF: 0.0000282 AC: 22 AN: 779718

Other (OTH) AF: 0.0000429 AC: 2 AN: 46630

⚠️ 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 Data not reliable, filtered out with message: AS_VQSR AF: 0.00000843 AC: 1 AN: 118670 Hom.: 0 Cov.: 20 AF XY: 0.0000173 AC XY: 1 AN XY: 57718

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

African (AFR) AF: 0.00 AC: 0 AN: 30968

American (AMR) AF: 0.00 AC: 0 AN: 11620

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2904

East Asian (EAS) AF: 0.00 AC: 0 AN: 4216

South Asian (SAS) AF: 0.00 AC: 0 AN: 3532

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8246

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 210

European-Non Finnish (NFE) AF: 0.0000183 AC: 1 AN: 54602

Other (OTH) AF: 0.00 AC: 0 AN: 1590

⚠️ 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: 0.00 Hom.: 49

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	0.0010
DANN	Benign	0.72
DEOGEN2	Benign	0.00067	T
Eigen	Benign	-2.8
Eigen_PC	Benign	-2.9
FATHMM_MKL	Benign	0.0031	N
LIST_S2	Benign	0.33	T
M_CAP	Benign	0.0024	T
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-0.95	T
PhyloP100		-13
PrimateAI	Benign	0.30	T
PROVEAN	Benign	0.16	N
REVEL	Uncertain	0.36
Sift	Benign	0.084	T
Sift4G	Benign	0.57	T
Polyphen		0.0	B
Vest4		0.065
MVP		0.088
MPC		0.54
ClinPred		0.13	T
GERP RS		-7.6
gMVP		0.11
Mutation Taster		=98/2	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: rs9274390; hg19: chr6-32632659; COSMIC: COSV66572934; COSMIC: COSV66572934;