chrX-114726960-G-A

Variant names:

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP7BS2

The NM_000868.4(HTR2C):c.24G>A(p.Val8Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000171 in 1,112,246 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. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000027 ( 0 hom., 1 hem., cov: 23)

Exomes 𝑓: 0.000016 ( 0 hom. 3 hem. )

Consequence

HTR2C
NM_000868.4 synonymous

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.14

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 -9 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.55).

BP7

Synonymous conserved (PhyloP=2.14 with no splicing effect.

BS2

High Hemizygotes in GnomAdExome4 at 3 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HTR2C	NM_000868.4 link	c.24G>A	p.Val8Val	synonymous_variant	Exon 3 of 6	ENST00000276198.6	NP_000859.2	P28335-1
HTR2C	NM_001256760.3 link	c.24G>A	p.Val8Val	synonymous_variant	Exon 4 of 7		NP_001243689.2	P28335-1
HTR2C	NM_001256761.3 link	c.24G>A	p.Val8Val	synonymous_variant	Exon 3 of 6		NP_001243690.2	P28335-2K9J958
LOC105373313	XR_001755943.2 link	n.728+3662C>T		intron_variant	Intron 4 of 4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
HTR2C	ENST00000276198.6 link	c.24G>A	p.Val8Val	synonymous_variant	Exon 3 of 6	1	NM_000868.4	ENSP00000276198.1	P28335-1
HTR2C	ENST00000371951.5 link	c.24G>A	p.Val8Val	synonymous_variant	Exon 4 of 7	1		ENSP00000361019.1	P28335-1
HTR2C	ENST00000371950.3 link	c.24G>A	p.Val8Val	synonymous_variant	Exon 3 of 6	1		ENSP00000361018.3	P28335-2

Frequencies

GnomAD3 genomes

AF:

0.0000269

AC:

AN:

111632

Hom.:

Cov.:

AF XY:

0.0000296

AC XY:

AN XY:

33826

show subpopulations

Gnomad AFR

AF:

0.0000326

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000376

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000246

AC:

AN:

122185

Hom.:

AF XY:

0.0000273

AC XY:

AN XY:

36671

show subpopulations

Gnomad AFR exome

AF:

0.00

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:

0.0000513

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000160

AC:

AN:

1000614

Hom.:

Cov.:

AF XY:

0.00000992

AC XY:

AN XY:

302272

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:

0.0000191

Gnomad4 OTH exome

AF:

0.0000236

GnomAD4 genome

AF:

0.0000269

AC:

AN:

111632

Hom.:

Cov.:

AF XY:

0.0000296

AC XY:

AN XY:

33826

show subpopulations

Gnomad4 AFR

AF:

0.0000326

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000376

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000214

Hom.:

Bravo

AF:

0.0000189

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

HTR2C-related disorder

Uncertain:1

Mar 28, 2023

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The HTR2C c.24G>A variant is not predicted to result in an amino acid change (p.=). This variant is predicted to introduce a cryptic splice site within exon 3 (Alamut Visual Plus v1.6.1). However, such computer prediction programs are imperfect. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0058% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/X-113961369-G-A). 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

BayesDel_noAF

Benign

-0.55

CADD

Benign

DANN

Benign

0.81

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.16

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