6-32664795-CACCTCTCCTCTG-C

Variant names:

• chr6-32664795-CACCTCTCCTCTG-C
• NM_002123.5:c.370_379+2delCAGAGGAGAGGT

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PP5_Moderate BS2

The NM_002123.5(HLA-DQB1):​c.370_379+2delCAGAGGAGAGGT​(p.Gln124fs) variant causes a frameshift, splice donor, splice region, intron change. The variant allele was found at a frequency of 0.0000563 in 922,916 control chromosomes in the GnomAD database, including 5 homozygotes. Variant has been reported in ClinVar as Likely pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 13)
  • Exomes 𝑓: 0.000056 (5 hom.)
  • Failed GnomAD Quality Control
• Consequence: HLA-DQB1 NM_002123.5 frameshift, splice_donor, splice_region, intron
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 5.84

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

Verdict is Likely_benign. Variant got -2 ACMG points.

• PP5: Variant 6-32664795-CACCTCTCCTCTG-C is Pathogenic according to our data. Variant chr6-32664795-CACCTCTCCTCTG-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3256932.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAdExome4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HLA-DQB1	NM_002123.5	c.370_379+2delCAGAGGAGAGGT	p.Gln124fs	frameshift_variant, splice_donor_variant, splice_region_variant, intron_variant	Exon 2 of 5	ENST00000434651.7	NP_002114.3
HLA-DQB1	NM_001243961.2	c.370_379+2delCAGAGGAGAGGT	p.Gln124fs	frameshift_variant, splice_donor_variant, splice_region_variant, intron_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.370_379+2delCAGAGGAGAGGT	p.Gln124fs	frameshift_variant, splice_donor_variant, splice_region_variant, intron_variant	Exon 2 of 5	6	NM_002123.5	ENSP00000407332.2
HLA-DQB1	ENST00000374943.8	c.370_379+2delCAGAGGAGAGGT	p.Gln124fs	frameshift_variant, splice_donor_variant, splice_region_variant, intron_variant	Exon 2 of 6	6		ENSP00000364080.4

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 111744 Hom.: 0 Cov.: 13 FAILED QC

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: 0.0000563 AC: 52 AN: 922916 Hom.: 5 AF XY: 0.0000855 AC XY: 40 AN XY: 468066

Gnomad4 AFR exome AF: 0.0000861

Gnomad4 AMR exome AF: 0.0000880

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000153

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000659

Gnomad4 OTH exome AF: 0.0000494

GnomAD4 genome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 111834 Hom.: 0 Cov.: 13 AF XY: 0.00 AC XY: 0 AN XY: 54410

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Susceptibility to severe COVID-19 Pathogenic:1

Jul 22, 2024

Molecular Medicine Center, Medical University of Sofia

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

Novel (unreported in gnomAD or dbSNP until April 2024) variant found in severely infected COVID-19 Bulgarian patients in a research study. Variant is classified as likely pathogenic according to the ACMG criteria: PM2,PVS1. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-32632572;