chr2-231115305-C-T

Position:

• chr2-231115305-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002807.4(PSMD1):​c.1884-23431C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.534 in 151,832 control chromosomes in the GnomAD database, including 24,446 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 0.53 (24446 hom., cov: 31)
• Consequence: PSMD1 NM_002807.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.178

Genes affected

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]

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.816 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HTR2B	NM_000867.5	c.353-1376G>A		intron_variant		ENST00000258400.4	NP_000858.3
PSMD1	NM_002807.4	c.1884-23431C>T		intron_variant		ENST00000308696.11	NP_002798.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HTR2B	ENST00000258400.4	c.353-1376G>A		intron_variant		1	NM_000867.5	ENSP00000258400	P1
PSMD1	ENST00000308696.11	c.1884-23431C>T		intron_variant		1	NM_002807.4	ENSP00000309474	P1

Frequencies

GnomAD3 genomes AF: 0.534 AC: 80970 AN: 151714 Hom.: 24393 Cov.: 31

Gnomad AFR AF: 0.823

Gnomad AMI AF: 0.391

Gnomad AMR AF: 0.405

Gnomad ASJ AF: 0.480

Gnomad EAS AF: 0.610

Gnomad SAS AF: 0.474

Gnomad FIN AF: 0.525

Gnomad MID AF: 0.468

Gnomad NFE AF: 0.392

Gnomad OTH AF: 0.499

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

GnomAD4 genome AF: 0.534 AC: 81072 AN: 151832 Hom.: 24446 Cov.: 31 AF XY: 0.536 AC XY: 39781 AN XY: 74182

Gnomad4 AFR AF: 0.823

Gnomad4 AMR AF: 0.404

Gnomad4 ASJ AF: 0.480

Gnomad4 EAS AF: 0.611

Gnomad4 SAS AF: 0.473

Gnomad4 FIN AF: 0.525

Gnomad4 NFE AF: 0.392

Gnomad4 OTH AF: 0.497

Alfa AF: 0.411 Hom.: 15732

Bravo AF: 0.536

Asia WGS AF: 0.600 AC: 2081 AN: 3472

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	7.4
DANN	Benign	0.72

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: rs10194776; hg19: chr2-231980019;