2-231109341-C-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_000867.5(HTR2B):c.622G>T(p.Val208Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00127 in 1,614,008 control chromosomes in the GnomAD database, including 26 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 0.0070 (18 hom., cov: 32)
  • Exomes 𝑓: 0.00067 (8 hom.)
• Consequence: HTR2B NM_000867.5 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.883

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=0.009016991).
• BP6: Variant 2-231109341-C-A is Benign according to our data. Variant chr2-231109341-C-A is described in ClinVar as [Benign]. Clinvar id is 709655.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00695 (1059/152312) while in subpopulation AFR AF= 0.0246 (1021/41558). AF 95% confidence interval is 0.0233. There are 18 homozygotes in gnomad4. There are 505 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 18 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HTR2B	NM_000867.5	c.622G>T	p.Val208Leu	missense_variant	4/4	ENST00000258400.4
PSMD1	NM_002807.4	c.1883+22160C>A		intron_variant		ENST00000308696.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HTR2B	ENST00000258400.4	c.622G>T	p.Val208Leu	missense_variant	4/4	1	NM_000867.5	P1
PSMD1	ENST00000308696.11	c.1883+22160C>A		intron_variant		1	NM_002807.4	P1

Frequencies

GnomAD3 genomes AF: 0.00694 AC: 1056 AN: 152194 Hom.: 18 Cov.: 32

Gnomad AFR AF: 0.0245

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00222

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00174 AC: 436 AN: 251000 Hom.: 3 AF XY: 0.00127 AC XY: 172 AN XY: 135648

Gnomad AFR exome AF: 0.0249

Gnomad AMR exome AF: 0.000666

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.000981

GnomAD4 exome AF: 0.000674 AC: 985 AN: 1461696 Hom.: 8 Cov.: 32 AF XY: 0.000564 AC XY: 410 AN XY: 727150

Gnomad4 AFR exome AF: 0.0257

Gnomad4 AMR exome AF: 0.000783

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000108

Gnomad4 OTH exome AF: 0.00124

GnomAD4 genome AF: 0.00695 AC: 1059 AN: 152312 Hom.: 18 Cov.: 32 AF XY: 0.00678 AC XY: 505 AN XY: 74482

Gnomad4 AFR AF: 0.0246

Gnomad4 AMR AF: 0.00216

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.000753 Hom.: 2

Bravo AF: 0.00787

ESP6500AA AF: 0.0293 AC: 129

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00222 AC: 269

Asia WGS AF: 0.00144 AC: 5 AN: 3478

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

Jul 15, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.73
Cadd	Benign	9.9
Dann	Benign	0.81
DEOGEN2	Benign	0.090	T
Eigen	Benign	-0.87
Eigen_PC	Benign	-0.72
FATHMM_MKL	Benign	0.37	N
LIST_S2	Benign	0.67	T
MetaRNN	Benign	0.0090	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.27	N
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.67	N
REVEL	Benign	0.083
Sift	Benign	0.39	T
Sift4G	Benign	0.38	T
Polyphen		0.0	B
Vest4		0.046
MutPred		0.61		Gain of catalytic residue at V208 (P = 0.0318);
MVP		0.48
MPC		0.14
ClinPred		0.0024	T
GERP RS		3.9
Varity_R		0.10
gMVP		0.67

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: rs61731725; hg19: chr2-231974055;