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GeneBe

X-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 (★).

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

1
13

Clinical Significance

Uncertain significance criteria provided, single submitter 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]

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 GnomAdExome at 4 gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
HTR2CNM_000868.4 linkuse as main transcriptc.181G>A p.Val61Ile missense_variant 4/6 ENST00000276198.6
LOC105373313XR_001755943.2 linkuse as main transcriptn.574-663C>T intron_variant, non_coding_transcript_variant
HTR2CNM_001256760.3 linkuse as main transcriptc.181G>A p.Val61Ile missense_variant 5/7
HTR2CNM_001256761.3 linkuse as main transcriptc.181G>A p.Val61Ile missense_variant 4/6

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
HTR2CENST00000276198.6 linkuse as main transcriptc.181G>A p.Val61Ile missense_variant 4/61 NM_000868.4 P1P28335-1
HTR2CENST00000371951.5 linkuse as main transcriptc.181G>A p.Val61Ile missense_variant 5/71 P1P28335-1
HTR2CENST00000371950.3 linkuse as main transcriptc.181G>A p.Val61Ile missense_variant 4/61 P28335-2

Frequencies

GnomAD3 genomes
AF:
0.0000995
AC:
11
AN:
110510
Hom.:
0
Cov.:
22
AF XY:
0.0000305
AC XY:
1
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:
17
AN:
183468
Hom.:
0
AF XY:
0.0000589
AC XY:
4
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:
84
AN:
1097648
Hom.:
0
Cov.:
31
AF XY:
0.0000661
AC XY:
24
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:
11
AN:
110510
Hom.:
0
Cov.:
22
AF XY:
0.0000305
AC XY:
1
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.:
0
Bravo
AF:
0.0000945
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000149
AC:
1
ExAC
AF:
0.0000988
AC:
12
EpiCase
AF:
0.00
EpiControl
AF:
0.000119

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 submitterclinical testingPreventionGenetics, part of Exact SciencesJan 31, 2024The 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
T
BayesDel_noAF
Benign
-0.85
Cadd
Benign
9.3
Dann
Uncertain
0.98
FATHMM_MKL
Benign
0.066
N
M_CAP
Benign
0.045
D
MetaRNN
Benign
0.020
T;T;T
MetaSVM
Benign
-1.0
T
MutationTaster
Benign
1.0
N;N;N
PrimateAI
Benign
0.34
T
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
T
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.

Other links and lift over

dbSNP: rs371347099; hg19: chrX-113965848; COSMIC: COSV99348797; API