X-114906602-T-C

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The ENST00000371950.3(HTR2C):c.469T>C(p.Tyr157His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000117 in 1,197,622 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 44 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/14 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00058 (0 hom., 18 hem., cov: 22)
  • Exomes 𝑓: 0.000069 (0 hom. 26 hem.)
• Consequence: HTR2C ENST00000371950.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.44

Genes affected

HTR2C (HGNC:5295): (5-hydroxytryptamine receptor 2C) This gene encodes a seven-transmembrane G-protein-coupled receptor. The encoded protein responds to signaling through the neurotransmitter serotonin. The mRNA of this gene is subject to multiple RNA editing events, where adenosine residues encoded by the genome are converted to inosines. RNA editing is predicted to alter the structure of the second intracellular loop, thereby generating alternate protein forms with decreased ability to interact with G proteins. Abnormalities in RNA editing of this gene have been detected in victims of suicide that suffer from depression. In addition, naturally-occuring variation in the promoter and 5' non-coding and coding regions of this gene may show statistically-significant association with mental illness and behavioral disorders. Alternative splicing results in multiple different transcript variants. [provided by RefSeq, Jan 2015]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009622276).
• BP6: Variant X-114906602-T-C is Benign according to our data. Variant chrX-114906602-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 3037881.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Hemizygotes in GnomAd at 18 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HTR2C	NM_000868.4	c.564T>C	p.Pro188=	synonymous_variant	6/6	ENST00000276198.6
HTR2C	NM_001256761.3	c.469T>C	p.Tyr157His	missense_variant	6/6
HTR2C	NM_001256760.3	c.564T>C	p.Pro188=	synonymous_variant	7/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HTR2C	ENST00000371950.3	c.469T>C	p.Tyr157His	missense_variant	6/6	1
HTR2C	ENST00000276198.6	c.564T>C	p.Pro188=	synonymous_variant	6/6	1	NM_000868.4	P1
HTR2C	ENST00000371951.5	c.564T>C	p.Pro188=	synonymous_variant	7/7	1		P1

Frequencies

GnomAD3 genomes AF: 0.000581 AC: 65 AN: 111879 Hom.: 0 Cov.: 22 AF XY: 0.000529 AC XY: 18 AN XY: 34051

Gnomad AFR AF: 0.00205

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000189

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000146 AC: 25 AN: 171595 Hom.: 0 AF XY: 0.000156 AC XY: 9 AN XY: 57859

Gnomad AFR exome AF: 0.00191

Gnomad AMR exome AF: 0.00

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000691 AC: 75 AN: 1085691 Hom.: 0 Cov.: 29 AF XY: 0.0000736 AC XY: 26 AN XY: 353145

Gnomad4 AFR exome AF: 0.00260

Gnomad4 AMR exome AF: 0.0000288

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.000132

GnomAD4 genome AF: 0.000581 AC: 65 AN: 111931 Hom.: 0 Cov.: 22 AF XY: 0.000528 AC XY: 18 AN XY: 34113

Gnomad4 AFR AF: 0.00204

Gnomad4 AMR AF: 0.000189

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: 0.00

Alfa AF: 0.000695 Hom.: 4

Bravo AF: 0.000642

ESP6500AA AF: 0.00183 AC: 7

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000140 AC: 17

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

HTR2C-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 14, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.51
Cadd	Benign	4.0
Dann	Benign	0.97
FATHMM_MKL	Benign	0.10	N
M_CAP	Benign	0.0077	T
MetaRNN	Benign	0.0096	T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	D;D;N
PROVEAN	Benign	0.37	N
REVEL	Benign	0.060
Sift	Benign	0.031	D
Sift4G	Uncertain	0.032	D
Vest4		0.19
MVP		0.44
ClinPred		0.0095	T
GERP RS		-4.7

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: rs144618891; hg19: chrX-114141165;