chrX-114731436-A-G

Position:

chrX-114731436-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_000868.4(HTR2C):c.178A>G(p.Ile60Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000181 in 110,738 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 11/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000018 ( 0 hom., 0 hem., cov: 22)

Exomes 𝑓: 9.1e-7 ( 0 hom. 1 hem. )

Failed GnomAD Quality Control

Consequence

HTR2C
NM_000868.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.31

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 Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.21965197).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
HTR2C	NM_000868.4 linkuse as main transcript	c.178A>G	p.Ile60Val	missense_variant	4/6	ENST00000276198.6
LOC105373313	XR_001755943.2 linkuse as main transcript	n.574-660T>C		intron_variant, non_coding_transcript_variant
HTR2C	NM_001256760.3 linkuse as main transcript	c.178A>G	p.Ile60Val	missense_variant	5/7
HTR2C	NM_001256761.3 linkuse as main transcript	c.178A>G	p.Ile60Val	missense_variant	4/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HTR2C	ENST00000276198.6 linkuse as main transcript	c.178A>G	p.Ile60Val	missense_variant	4/6	1	NM_000868.4	P1	P28335-1
HTR2C	ENST00000371951.5 linkuse as main transcript	c.178A>G	p.Ile60Val	missense_variant	5/7	1		P1	P28335-1
HTR2C	ENST00000371950.3 linkuse as main transcript	c.178A>G	p.Ile60Val	missense_variant	4/6	1			P28335-2

Frequencies

GnomAD3 genomes

AF:

0.0000181

AC:

AN:

110738

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

32962

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000968

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:

0.000671

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

9.11e-7

AC:

AN:

1097724

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

363080

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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:

0.0000217

GnomAD4 genome

AF:

0.0000181

AC:

AN:

110738

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

32962

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000968

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:

0.000671

Bravo

AF:

0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

HTR2C-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 22, 2023

The HTR2C c.178A>G variant is predicted to result in the amino acid substitution p.Ile60Val. To our knowledge, this variant has not been reported in the literature or in a large population database, indicating this variant is rare. 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

0.12

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Benign

-0.46

CADD

Benign

DANN

Uncertain

1.0

FATHMM_MKL

Uncertain

0.95

M_CAP

Benign

0.015

MetaRNN

Benign

0.22

T;T;T

MetaSVM

Benign

-1.0

MutationTaster

Benign

0.86

N;N;N

PrimateAI

Benign

0.46

PROVEAN

Benign

-0.25

N;N;N

REVEL

Benign

0.19

Sift

Benign

0.18

T;T;T

Sift4G

Benign

0.25

T;T;T

Vest4

0.40

MutPred

0.33

Gain of catalytic residue at I60 (P = 0.0054);Gain of catalytic residue at I60 (P = 0.0054);Gain of catalytic residue at I60 (P = 0.0054);

MVP

0.21

MPC

0.35

ClinPred

0.71

GERP RS

5.4

gMVP

0.42

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