rs2071627

chr6-32841446-C-Achr6-32841446-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_148919.4(PSMB8):c.742+85G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.395 in 1,392,178 control chromosomes in the GnomAD database, including 111,468 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.36 (10304 hom., cov: 32)
  • Exomes 𝑓: 0.40 (101164 hom.)
• Consequence: PSMB8 NM_148919.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0200

Genes affected

PSMB8 (HGNC:9545): (proteasome 20S subunit beta 8) The proteasome is a multicatalytic proteinase complex with a highly ordered ring-shaped 20S core structure. The core structure is composed of 4 rings of 28 non-identical subunits; 2 rings are composed of 7 alpha subunits and 2 rings are composed of 7 beta subunits. Proteasomes are distributed throughout eukaryotic cells at a high concentration and cleave peptides in an ATP/ubiquitin-dependent process in a non-lysosomal pathway. An essential function of a modified proteasome, the immunoproteasome, is the processing of class I MHC peptides. This gene encodes a member of the proteasome B-type family, also known as the T1B family, that is a 20S core beta subunit. This gene is located in the class II region of the MHC (major histocompatibility complex). Expression of this gene is induced by gamma interferon and this gene product replaces catalytic subunit 3 (proteasome beta 5 subunit) in the immunoproteasome. Proteolytic processing is required to generate a mature subunit. Two alternative transcripts encoding two isoforms have been identified; both isoforms are processed to yield the same mature subunit. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 6-32841446-C-A is Benign according to our data. Variant chr6-32841446-C-A is described in ClinVar as [Benign]. Clinvar id is 1239292.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.411 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PSMB8	NM_148919.4	c.742+85G>T		intron_variant		ENST00000374882.8
PSMB8	NM_004159.5	c.730+85G>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PSMB8	ENST00000374882.8	c.742+85G>T		intron_variant		1	NM_148919.4	P1

Frequencies

GnomAD3 genomes AF: 0.363 AC: 55164 AN: 151916 Hom.: 10309 Cov.: 32

Gnomad AFR AF: 0.305

Gnomad AMI AF: 0.478

Gnomad AMR AF: 0.324

Gnomad ASJ AF: 0.327

Gnomad EAS AF: 0.230

Gnomad SAS AF: 0.352

Gnomad FIN AF: 0.381

Gnomad MID AF: 0.506

Gnomad NFE AF: 0.415

Gnomad OTH AF: 0.372

GnomAD4 exome AF: 0.399 AC: 494656 AN: 1240144 Hom.: 101164 AF XY: 0.398 AC XY: 249768 AN XY: 627534

Gnomad4 AFR exome AF: 0.306

Gnomad4 AMR exome AF: 0.300

Gnomad4 ASJ exome AF: 0.342

Gnomad4 EAS exome AF: 0.250

Gnomad4 SAS exome AF: 0.333

Gnomad4 FIN exome AF: 0.378

Gnomad4 NFE exome AF: 0.421

Gnomad4 OTH exome AF: 0.395

GnomAD4 genome AF: 0.363 AC: 55156 AN: 152034 Hom.: 10304 Cov.: 32 AF XY: 0.358 AC XY: 26599 AN XY: 74326

Gnomad4 AFR AF: 0.304

Gnomad4 AMR AF: 0.323

Gnomad4 ASJ AF: 0.327

Gnomad4 EAS AF: 0.231

Gnomad4 SAS AF: 0.350

Gnomad4 FIN AF: 0.381

Gnomad4 NFE AF: 0.415

Gnomad4 OTH AF: 0.368

Alfa AF: 0.240 Hom.: 564

Bravo AF: 0.355

Asia WGS AF: 0.273 AC: 951 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Nov 14, 2023

This variant is classified as Benign based on local population frequency. This variant was detected in 46% of patients studied by a panel of primary immunodeficiencies. Number of patients: 44. Only high quality variants are reported. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 12, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
Cadd	Benign	2.5
Dann	Benign	0.79

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

LitVar

Other links and lift over

dbSNP: rs2071627; hg19: chr6-32809223;