NM_000868.4:c.4G>A

Variant names:

• chrX-114726940-G-A
• rs200113008
• NM_000868.4:c.4G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_000868.4(HTR2C):​c.4G>A​(p.Val2Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000982 in 1,018,330 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 9.8e-7 (0 hom. 1 hem.)
• Consequence: HTR2C NM_000868.4 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 2.78
• Publications: 0 publications found

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]

ENSG00000306059 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000868.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HTR2C	NM_000868.4	MANE Select	c.4G>A	p.Val2Met	missense	Exon 3 of 6	NP_000859.2	P28335-1
	HTR2C	NM_001256760.3		c.4G>A	p.Val2Met	missense	Exon 4 of 7	NP_001243689.2	P28335-1
	HTR2C	NM_001256761.3		c.4G>A	p.Val2Met	missense	Exon 3 of 6	NP_001243690.2	P28335-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HTR2C	ENST00000276198.6	TSL:1 MANE Select	c.4G>A	p.Val2Met	missense	Exon 3 of 6	ENSP00000276198.1	P28335-1
	HTR2C	ENST00000371951.5	TSL:1	c.4G>A	p.Val2Met	missense	Exon 4 of 7	ENSP00000361019.1	P28335-1
	HTR2C	ENST00000371950.3	TSL:1	c.4G>A	p.Val2Met	missense	Exon 3 of 6	ENSP00000361018.3	P28335-2

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 9.82e-7 AC: 1 AN: 1018330 Hom.: 0 Cov.: 21 AF XY: 0.00000317 AC XY: 1 AN XY: 315078

African (AFR) AF: 0.00 AC: 0 AN: 22196

American (AMR) AF: 0.00 AC: 0 AN: 22719

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17591

East Asian (EAS) AF: 0.00 AC: 0 AN: 26551

South Asian (SAS) AF: 0.00 AC: 0 AN: 43973

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39862

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3962

European-Non Finnish (NFE) AF: 0.00000125 AC: 1 AN: 798474

Other (OTH) AF: 0.00 AC: 0 AN: 43002

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	1	-	HTR2C-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.077	T
BayesDel_noAF	Benign	-0.35
CADD	Uncertain	24
DANN	Uncertain	1.0
FATHMM_MKL	Benign	0.67	D
M_CAP	Benign	0.018	T
MetaRNN	Uncertain	0.45	T
MetaSVM	Benign	-1.0	T
PhyloP100		2.8
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-0.56	N
REVEL	Benign	0.14
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Vest4		0.58
MutPred		0.20		Gain of disorder (P = 0.0892)
MVP		0.93
MPC		1.1
ClinPred		0.59	D
GERP RS		2.9
gMVP		0.32
Mutation Taster		=92/8	polymorphism

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

Other links and lift over

dbSNP: rs200113008; hg19: chrX-113961349;