X-114726940-G-A

Position:

• chrX-114726940-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The ENST00000276198.6(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. 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 ENST00000276198.6 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 2.78

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]

LOC105373313 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HTR2C	NM_000868.4	c.4G>A	p.Val2Met	missense_variant	3/6	ENST00000276198.6	NP_000859.2
LOC105373313	XR_001755943.2	n.728+3682C>T		intron_variant, non_coding_transcript_variant
HTR2C	NM_001256760.3	c.4G>A	p.Val2Met	missense_variant	4/7		NP_001243689.2
HTR2C	NM_001256761.3	c.4G>A	p.Val2Met	missense_variant	3/6		NP_001243690.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HTR2C	ENST00000276198.6	c.4G>A	p.Val2Met	missense_variant	3/6	1	NM_000868.4	ENSP00000276198	P1
HTR2C	ENST00000371951.5	c.4G>A	p.Val2Met	missense_variant	4/7	1		ENSP00000361019	P1
HTR2C	ENST00000371950.3	c.4G>A	p.Val2Met	missense_variant	3/6	1		ENSP00000361018

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

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: 0.00000125

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

HTR2C-related disorder Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 14, 2024

The HTR2C c.4G>A variant is predicted to result in the amino acid substitution p.Val2Met. To our knowledge, this variant has not been reported in the literature or in a large population database, indicating this variant is rare. 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	0.16
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;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.99	N;N;N
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-0.56	N;N;N
REVEL	Benign	0.14
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Vest4		0.58
MutPred		0.20		Gain of disorder (P = 0.0892);Gain of disorder (P = 0.0892);Gain of disorder (P = 0.0892);
MVP		0.93
MPC		1.1
ClinPred		0.59	D
GERP RS		2.9
gMVP		0.32

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

Other links and lift over

dbSNP: rs200113008; hg19: chrX-113961349;