X-114731439-G-A

Position:

chrX-114731439-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_000868.4(HTR2C):c.181G>A(p.Val61Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000786 in 1,208,158 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 25 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

Frequency

Genomes: 𝑓 0.00010 ( 0 hom., 1 hem., cov: 22)

Exomes 𝑓: 0.000077 ( 0 hom. 24 hem. )

Consequence

HTR2C
NM_000868.4 missense

Scores

Clinical Significance

Uncertain significance no assertion criteria provided U:1

Conservation

PhyloP100: -1.35

Variant links:

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]

HTR2C links:

LOC105373313 (HGNC:):

LOC105373313 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.020413846).

BS2

High Hemizygotes in GnomAdExome4 at 24 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
HTR2C	NM_000868.4 linkuse as main transcript	c.181G>A	p.Val61Ile	missense_variant	4/6	ENST00000276198.6	NP_000859.2
LOC105373313	XR_001755943.2 linkuse as main transcript	n.574-663C>T		intron_variant, non_coding_transcript_variant
HTR2C	NM_001256760.3 linkuse as main transcript	c.181G>A	p.Val61Ile	missense_variant	5/7		NP_001243689.2
HTR2C	NM_001256761.3 linkuse as main transcript	c.181G>A	p.Val61Ile	missense_variant	4/6		NP_001243690.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HTR2C	ENST00000276198.6 linkuse as main transcript	c.181G>A	p.Val61Ile	missense_variant	4/6	1	NM_000868.4	ENSP00000276198	P1	P28335-1
HTR2C	ENST00000371951.5 linkuse as main transcript	c.181G>A	p.Val61Ile	missense_variant	5/7	1		ENSP00000361019	P1	P28335-1
HTR2C	ENST00000371950.3 linkuse as main transcript	c.181G>A	p.Val61Ile	missense_variant	4/6	1		ENSP00000361018		P28335-2

Frequencies

GnomAD3 genomes

AF:

0.0000995

AC:

AN:

110510

Hom.:

Cov.:

AF XY:

0.0000305

AC XY:

AN XY:

32768

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000873

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:

0.0000378

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000927

AC:

AN:

183468

Hom.:

AF XY:

0.0000589

AC XY:

AN XY:

67904

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000438

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:

0.0000244

Gnomad OTH exome

AF:

0.000662

GnomAD4 exome

AF:

0.0000765

AC:

AN:

1097648

Hom.:

Cov.:

AF XY:

0.0000661

AC XY:

AN XY:

363014

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000369

Gnomad4 ASJ exome

AF:

0.0000516

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000820

Gnomad4 OTH exome

AF:

0.0000217

GnomAD4 genome

AF:

0.0000995

AC:

AN:

110510

Hom.:

Cov.:

AF XY:

0.0000305

AC XY:

AN XY:

32768

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000873

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000378

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000425

Hom.:

Bravo

AF:

0.0000945

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000149

AC:

ExAC

AF:

0.0000988

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

HTR2C-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 17, 2024

The HTR2C c.181G>A variant is predicted to result in the amino acid substitution p.Val61Ile. This variant was previously identified in individuals with obesity; however, this variant was not associated with BMI in single-variant analyses (He et al. 2022. PubMed ID: 36536256). Additionally, this variant is reported in 0.043% of alleles in individuals of Latino descent in gnomAD, including four hemizygotes. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.071

BayesDel_addAF

Benign

-0.64

BayesDel_noAF

Benign

-0.85

CADD

Benign

9.3

DANN

Uncertain

0.98

FATHMM_MKL

Benign

0.066

M_CAP

Benign

0.045

MetaRNN

Benign

0.020

T;T;T

MetaSVM

Benign

-1.0

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Benign

0.34

PROVEAN

Benign

0.27

N;N;N

REVEL

Benign

0.013

Sift

Benign

0.30

T;T;T

Sift4G

Benign

0.37

T;T;T

Vest4

0.088

MVP

0.21

MPC

0.30

ClinPred

0.028

GERP RS

1.4

gMVP

0.13

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over