2-231108649-G-A

Position:

• chr2-231108649-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000867.5(HTR2B):​c.1314C>T​(p.Asn438=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0057 in 1,614,022 control chromosomes in the GnomAD database, including 465 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.030 (246 hom., cov: 32)
  • Exomes 𝑓: 0.0032 (219 hom.)
• Consequence: HTR2B NM_000867.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.685

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant 2-231108649-G-A is Benign according to our data. Variant chr2-231108649-G-A is described in ClinVar as [Benign]. Clinvar id is 779323.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.685 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.101 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HTR2B	NM_000867.5	c.1314C>T	p.Asn438=	synonymous_variant	4/4	ENST00000258400.4	NP_000858.3
PSMD1	NM_002807.4	c.1883+21468G>A		intron_variant		ENST00000308696.11	NP_002798.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HTR2B	ENST00000258400.4	c.1314C>T	p.Asn438=	synonymous_variant	4/4	1	NM_000867.5	ENSP00000258400	P1
PSMD1	ENST00000308696.11	c.1883+21468G>A		intron_variant		1	NM_002807.4	ENSP00000309474	P1

Frequencies

GnomAD3 genomes AF: 0.0296 AC: 4502 AN: 152104 Hom.: 242 Cov.: 32

Gnomad AFR AF: 0.103

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0112

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000309

Gnomad OTH AF: 0.0191

GnomAD3 exomes AF: 0.00793 AC: 1991 AN: 251050 Hom.: 107 AF XY: 0.00615 AC XY: 835 AN XY: 135678

Gnomad AFR exome AF: 0.106

Gnomad AMR exome AF: 0.00489

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000545

Gnomad SAS exome AF: 0.00150

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000229

Gnomad OTH exome AF: 0.00424

GnomAD4 exome AF: 0.00319 AC: 4668 AN: 1461800 Hom.: 219 Cov.: 32 AF XY: 0.00281 AC XY: 2044 AN XY: 727202

Gnomad4 AFR exome AF: 0.109

Gnomad4 AMR exome AF: 0.00521

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.00181

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000129

Gnomad4 OTH exome AF: 0.00752

GnomAD4 genome AF: 0.0298 AC: 4535 AN: 152222 Hom.: 246 Cov.: 32 AF XY: 0.0287 AC XY: 2138 AN XY: 74436

Gnomad4 AFR AF: 0.103

Gnomad4 AMR AF: 0.0112

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000579

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000309

Gnomad4 OTH AF: 0.0189

Alfa AF: 0.0137 Hom.: 57

Bravo AF: 0.0342

Asia WGS AF: 0.0110 AC: 38 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jun 18, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	3.0
DANN	Benign	0.87

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: rs61731723; hg19: chr2-231973363;