2-231123613-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000867.5(HTR2B):c.152G>A(p.Gly51Glu) variant causes a missense change. The variant allele was found at a frequency of 0.00415 in 1,614,040 control chromosomes in the GnomAD database, including 257 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.022 (136 hom., cov: 32)
  • Exomes 𝑓: 0.0023 (121 hom.)
• Consequence: HTR2B NM_000867.5 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.59

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.001858443).
• BP6: Variant 2-231123613-C-T is Benign according to our data. Variant chr2-231123613-C-T is described in ClinVar as [Benign]. Clinvar id is 779324.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0744 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HTR2B	NM_000867.5	c.152G>A	p.Gly51Glu	missense_variant	2/4	ENST00000258400.4
PSMD1	NM_002807.4	c.1884-15123C>T		intron_variant		ENST00000308696.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HTR2B	ENST00000258400.4	c.152G>A	p.Gly51Glu	missense_variant	2/4	1	NM_000867.5	P1
PSMD1	ENST00000308696.11	c.1884-15123C>T		intron_variant		1	NM_002807.4	P1

Frequencies

GnomAD3 genomes AF: 0.0220 AC: 3351 AN: 152132 Hom.: 135 Cov.: 32

Gnomad AFR AF: 0.0764

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00943

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.0148

GnomAD3 exomes AF: 0.00573 AC: 1441 AN: 251338 Hom.: 54 AF XY: 0.00430 AC XY: 584 AN XY: 135836

Gnomad AFR exome AF: 0.0784

Gnomad AMR exome AF: 0.00356

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000141

Gnomad OTH exome AF: 0.00342

GnomAD4 exome AF: 0.00227 AC: 3322 AN: 1461790 Hom.: 121 Cov.: 32 AF XY: 0.00193 AC XY: 1403 AN XY: 727198

Gnomad4 AFR exome AF: 0.0810

Gnomad4 AMR exome AF: 0.00367

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000128

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000944

Gnomad4 OTH exome AF: 0.00505

GnomAD4 genome AF: 0.0221 AC: 3372 AN: 152250 Hom.: 136 Cov.: 32 AF XY: 0.0210 AC XY: 1561 AN XY: 74458

Gnomad4 AFR AF: 0.0766

Gnomad4 AMR AF: 0.00942

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000206

Gnomad4 OTH AF: 0.0147

Alfa AF: 0.00132 Hom.: 1

Bravo AF: 0.0257

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.0722 AC: 318

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00700 AC: 850

Asia WGS AF: 0.00635 AC: 22 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jun 18, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.62
Cadd	Benign	19
Dann	Benign	0.96
DEOGEN2	Benign	0.090	T
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.049
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.62	T
MetaRNN	Benign	0.0019	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.81	L
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.27	N
REVEL	Benign	0.11
Sift	Benign	0.095	T
Sift4G	Benign	0.10	T
Polyphen		0.0020	B
Vest4		0.42
MVP		0.80
MPC		0.19
ClinPred		0.0061	T
GERP RS		4.8
Varity_R		0.22
gMVP		0.57

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs61731726; hg19: chr2-231988327;