2-231116063-A-G

Variant names:

• chr2-231116063-A-G
• rs16827801
• NM_002807.4:c.1884-22673A>G

Variant summary

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

The NM_002807.4(PSMD1):​c.1884-22673A>G 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 151,830 control chromosomes in the GnomAD database, including 13,181 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.40 (13181 hom., cov: 31)
• Consequence: PSMD1 NM_002807.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0530
• Publications: 13 publications found

Genes affected

PSMD1 (HGNC:9554): (proteasome 26S subunit, non-ATPase 1) The 26S proteasome is a multicatalytic proteinase complex with a highly ordered structure composed of 2 complexes, a 20S core and a 19S regulator. The 20S core 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. The 19S regulator is composed of a base, which contains 6 ATPase subunits and 2 non-ATPase subunits, and a lid, which contains up to 10 non-ATPase 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 the largest non-ATPase subunit of the 19S regulator lid, which is responsible for substrate recognition and binding. There is evidence that this proteasome and its subunits interact with viral proteins, including those of coronaviruses. Alternatively spliced transcript variants have been found for this gene.[provided by RefSeq, Aug 2020]

HTR2B (HGNC:5294): (5-hydroxytryptamine receptor 2B) This gene encodes one of the several different receptors for 5-hydroxytryptamine (serotonin) that belongs to the G-protein coupled receptor 1 family. Serotonin is a biogenic hormone that functions as a neurotransmitter, a hormone, and a mitogen. Serotonin receptors mediate many of the central and peripheral physiologic functions of serotonin, including regulation of cardiovascular functions and impulsive behavior. Population and family-based analyses of a minor allele (glutamine-to-stop substitution, designated Q20*) which blocks expression of this protein, and knockout studies in mice, suggest a role for this gene in impulsivity. However, other factors, such as elevated testosterone levels, may also be involved. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Mar 2016]

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.571 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002807.4. 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
	PSMD1	NM_002807.4	MANE Select	c.1884-22673A>G		intron	N/A	NP_002798.2
	HTR2B	NM_000867.5	MANE Select	c.353-2134T>C		intron	N/A	NP_000858.3
	PSMD1	NM_001191037.2		c.1884-22673A>G		intron	N/A	NP_001177966.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PSMD1	ENST00000308696.11	TSL:1 MANE Select	c.1884-22673A>G		intron	N/A	ENSP00000309474.6
	HTR2B	ENST00000258400.4	TSL:1 MANE Select	c.353-2134T>C		intron	N/A	ENSP00000258400.3
	PSMD1	ENST00000431051.6	TSL:1	n.*1567-22673A>G		intron	N/A	ENSP00000400483.1

Frequencies

GnomAD3 genomes AF: 0.395 AC: 59948 AN: 151712 Hom.: 13171 Cov.: 31

Gnomad AFR AF: 0.577

Gnomad AMI AF: 0.372

Gnomad AMR AF: 0.323

Gnomad ASJ AF: 0.380

Gnomad EAS AF: 0.498

Gnomad SAS AF: 0.420

Gnomad FIN AF: 0.416

Gnomad MID AF: 0.427

Gnomad NFE AF: 0.289

Gnomad OTH AF: 0.390

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.395 AC: 59999 AN: 151830 Hom.: 13181 Cov.: 31 AF XY: 0.400 AC XY: 29679 AN XY: 74186

African (AFR) AF: 0.577 AC: 23883 AN: 41378

American (AMR) AF: 0.322 AC: 4913 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.380 AC: 1318 AN: 3464

East Asian (EAS) AF: 0.499 AC: 2573 AN: 5152

South Asian (SAS) AF: 0.419 AC: 2015 AN: 4814

European-Finnish (FIN) AF: 0.416 AC: 4394 AN: 10554

Middle Eastern (MID) AF: 0.446 AC: 131 AN: 294

European-Non Finnish (NFE) AF: 0.289 AC: 19615 AN: 67900

Other (OTH) AF: 0.389 AC: 819 AN: 2108

Alfa AF: 0.303 Hom.: 7654

Bravo AF: 0.395

Asia WGS AF: 0.486 AC: 1689 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	3.9
DANN	Benign	0.82
PhyloP100		0.053
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: rs16827801; hg19: chr2-231980777;