X-114906698-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Moderate BP6_Moderate BS2

The ENST00000371950.3(HTR2C):c.565C>T(p.Arg189Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000019 in 1,208,785 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 4 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 11/14 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000018 (0 hom., 1 hem., cov: 22)
  • Exomes 𝑓: 0.000019 (0 hom. 3 hem.)
• Consequence: HTR2C ENST00000371950.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.154

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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.20823234).
• BP6: Variant X-114906698-C-T is Benign according to our data. Variant chrX-114906698-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 3044760.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Hemizygotes in GnomAdExome at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HTR2C	NM_000868.4	c.660C>T	p.Phe220=	synonymous_variant	6/6	ENST00000276198.6
HTR2C	NM_001256761.3	c.565C>T	p.Arg189Cys	missense_variant	6/6
HTR2C	NM_001256760.3	c.660C>T	p.Phe220=	synonymous_variant	7/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HTR2C	ENST00000371950.3	c.565C>T	p.Arg189Cys	missense_variant	6/6	1
HTR2C	ENST00000276198.6	c.660C>T	p.Phe220=	synonymous_variant	6/6	1	NM_000868.4	P1
HTR2C	ENST00000371951.5	c.660C>T	p.Phe220=	synonymous_variant	7/7	1		P1

Frequencies

GnomAD3 genomes AF: 0.0000180 AC: 2 AN: 111117 Hom.: 0 Cov.: 22 AF XY: 0.0000300 AC XY: 1 AN XY: 33331

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000192

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: 0.0000546 AC: 10 AN: 183247 Hom.: 0 AF XY: 0.0000295 AC XY: 2 AN XY: 67745

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000292

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000144

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: 0.0000191 AC: 21 AN: 1097613 Hom.: 0 Cov.: 30 AF XY: 0.00000826 AC XY: 3 AN XY: 362989

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000426

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000132

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000119

Gnomad4 OTH exome AF: 0.0000217

GnomAD4 genome AF: 0.0000180 AC: 2 AN: 111172 Hom.: 0 Cov.: 22 AF XY: 0.0000299 AC XY: 1 AN XY: 33396

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000191

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

Bravo AF: 0.0000302

ExAC AF: 0.0000247 AC: 3

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

Nov 17, 2023

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	-0.29	T
BayesDel_noAF	Benign	-0.36
Cadd	Benign	9.8
Dann	Uncertain	0.99
FATHMM_MKL	Benign	0.72	D
M_CAP	Benign	0.040	D
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-0.93	T
MutationTaster	Benign	0.73	D;D;D
PROVEAN	Benign	-0.34	N
REVEL	Benign	0.097
Sift	Uncertain	0.015	D
Sift4G	Uncertain	0.0060	D
Vest4		0.20
MutPred		0.64		Loss of MoRF binding (P = 0.007);
MVP		0.91
ClinPred		0.033	T
GERP RS		4.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs781957272; hg19: chrX-114141261; COSMIC: COSV52218630;