rs782363497

Variant names:

• chrX-114726960-G-A
• rs782363497
• NM_000868.4:c.24G>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP7 BS2

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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.14
• 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: Benign. The variant received -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

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.24G>A	p.Val8Val	synonymous	Exon 3 of 6	NP_000859.2	P28335-1
	HTR2C	NM_001256760.3		c.24G>A	p.Val8Val	synonymous	Exon 4 of 7	NP_001243689.2	P28335-1
	HTR2C	NM_001256761.3		c.24G>A	p.Val8Val	synonymous	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.24G>A	p.Val8Val	synonymous	Exon 3 of 6	ENSP00000276198.1	P28335-1
	HTR2C	ENST00000371951.5	TSL:1	c.24G>A	p.Val8Val	synonymous	Exon 4 of 7	ENSP00000361019.1	P28335-1
	HTR2C	ENST00000371950.3	TSL:1	c.24G>A	p.Val8Val	synonymous	Exon 3 of 6	ENSP00000361018.3	P28335-2

Frequencies

GnomAD3 genomes AF: 0.0000269 AC: 3 AN: 111632 Hom.: 0 Cov.: 23

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

GnomAD2 exomes AF: 0.0000246 AC: 3 AN: 122185 AF XY: 0.0000273

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000513

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000160 AC: 16 AN: 1000614 Hom.: 0 Cov.: 20 AF XY: 0.00000992 AC XY: 3 AN XY: 302272

African (AFR) AF: 0.00 AC: 0 AN: 21590

American (AMR) AF: 0.00 AC: 0 AN: 21562

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17324

East Asian (EAS) AF: 0.00 AC: 0 AN: 26221

South Asian (SAS) AF: 0.00 AC: 0 AN: 42987

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39770

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3917

European-Non Finnish (NFE) AF: 0.0000191 AC: 15 AN: 784881

Other (OTH) AF: 0.0000236 AC: 1 AN: 42362

GnomAD4 genome AF: 0.0000269 AC: 3 AN: 111632 Hom.: 0 Cov.: 23 AF XY: 0.0000296 AC XY: 1 AN XY: 33826

African (AFR) AF: 0.0000326 AC: 1 AN: 30706

American (AMR) AF: 0.00 AC: 0 AN: 10455

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2643

East Asian (EAS) AF: 0.00 AC: 0 AN: 3559

South Asian (SAS) AF: 0.00 AC: 0 AN: 2678

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6009

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 238

European-Non Finnish (NFE) AF: 0.0000376 AC: 2 AN: 53162

Other (OTH) AF: 0.00 AC: 0 AN: 1493

Alfa AF: 0.000214 Hom.: 1

Bravo AF: 0.0000189

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	12
DANN	Benign	0.81
PhyloP100		2.1
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs782363497; hg19: chrX-113961369;