X-114726944-A-G

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP3BS2

The NM_000868.4(HTR2C):c.8A>G(p.Asn3Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000248 in 1,130,825 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 0.00017 ( 0 hom., 4 hem., cov: 23)

Exomes 𝑓: 0.0000088 ( 0 hom. 0 hem. )

Consequence

HTR2C
NM_000868.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.64

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 Likely_benign. Variant got -3 ACMG points.

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

BS2

High Hemizygotes in GnomAd at 4 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
HTR2C	NM_000868.4 linkuse as main transcript	c.8A>G	p.Asn3Ser	missense_variant	3/6	ENST00000276198.6
LOC105373313	XR_001755943.2 linkuse as main transcript	n.728+3678T>C		intron_variant, non_coding_transcript_variant
HTR2C	NM_001256760.3 linkuse as main transcript	c.8A>G	p.Asn3Ser	missense_variant	4/7
HTR2C	NM_001256761.3 linkuse as main transcript	c.8A>G	p.Asn3Ser	missense_variant	3/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HTR2C	ENST00000276198.6 linkuse as main transcript	c.8A>G	p.Asn3Ser	missense_variant	3/6	1	NM_000868.4	P1	P28335-1
HTR2C	ENST00000371951.5 linkuse as main transcript	c.8A>G	p.Asn3Ser	missense_variant	4/7	1		P1	P28335-1
HTR2C	ENST00000371950.3 linkuse as main transcript	c.8A>G	p.Asn3Ser	missense_variant	3/6	1			P28335-2

Frequencies

GnomAD3 genomes

AF:

0.000170

AC:

AN:

111929

Hom.:

Cov.:

AF XY:

0.000117

AC XY:

AN XY:

34077

show subpopulations

Gnomad AFR

AF:

0.000584

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:

0.00

Gnomad OTH

AF:

0.000662

GnomAD3 exomes

AF:

0.0000637

AC:

AN:

125582

Hom.:

AF XY:

0.0000266

AC XY:

AN XY:

37562

show subpopulations

Gnomad AFR exome

AF:

0.000871

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000883

AC:

AN:

1018896

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

315686

show subpopulations

Gnomad4 AFR exome

AF:

0.000405

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:

0.00

GnomAD4 genome

AF:

0.000170

AC:

AN:

111929

Hom.:

Cov.:

AF XY:

0.000117

AC XY:

AN XY:

34077

show subpopulations

Gnomad4 AFR

AF:

0.000584

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:

0.00

Gnomad4 OTH

AF:

0.000662

Alfa

AF:

0.0000870

Hom.:

Bravo

AF:

0.000151

ESP6500AA

AF:

0.000782

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000578

AC:

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

Nov 20, 2023

The HTR2C c.8A>G variant is predicted to result in the amino acid substitution p.Asn3Ser. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.073% of alleles in individuals of African descent in gnomAD. 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

0.077

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.53

Cadd

Uncertain

Dann

Uncertain

1.0

FATHMM_MKL

Uncertain

0.78

M_CAP

Benign

0.014

MetaRNN

Benign

0.11

T;T;T

MetaSVM

Benign

-1.1

MutationTaster

Benign

0.98

N;N;N

PrimateAI

Uncertain

0.58

PROVEAN

Benign

-0.50

N;N;N

REVEL

Benign

0.037

Sift

Pathogenic

0.0

D;D;D

Sift4G

Pathogenic

0.0

D;D;T

Vest4

0.38

MVP

0.95

MPC

0.95

ClinPred

0.21

GERP RS

2.5

gMVP

0.35

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.51

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.51

Position offset: -5

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