X-114731461-T-C

Position:

• chrX-114731461-T-C

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_000868.4(HTR2C):​c.203T>C​(p.Ile68Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000273 in 1,097,011 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000027 (0 hom. 2 hem.)
• Consequence: HTR2C NM_000868.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.02

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 Likely_benign. Variant got -4 ACMG points.

• BS2: High Hemizygotes in GnomAdExome4 at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HTR2C	NM_000868.4	c.203T>C	p.Ile68Thr	missense_variant	4/6	ENST00000276198.6
LOC105373313	XR_001755943.2	n.574-685A>G		intron_variant, non_coding_transcript_variant
HTR2C	NM_001256760.3	c.203T>C	p.Ile68Thr	missense_variant	5/7
HTR2C	NM_001256761.3	c.203T>C	p.Ile68Thr	missense_variant	4/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HTR2C	ENST00000276198.6	c.203T>C	p.Ile68Thr	missense_variant	4/6	1	NM_000868.4	P1
HTR2C	ENST00000371951.5	c.203T>C	p.Ile68Thr	missense_variant	5/7	1		P1
HTR2C	ENST00000371950.3	c.203T>C	p.Ile68Thr	missense_variant	4/6	1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.00000273 AC: 3 AN: 1097011 Hom.: 0 Cov.: 31 AF XY: 0.00000552 AC XY: 2 AN XY: 362377

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: 0.00000357

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 12, 2023

The c.203T>C (p.I68T) alteration is located in exon 4 (coding exon 2) of the HTR2C gene. This alteration results from a T to C substitution at nucleotide position 203, causing the isoleucine (I) at amino acid position 68 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Benign	-0.038	T
BayesDel_noAF	Benign	-0.29
CADD	Uncertain	26
DANN	Uncertain	1.0
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Benign	0.038	D
MetaRNN	Uncertain	0.59	D;D;D
MetaSVM	Benign	-0.85	T
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-2.8	D;D;D
REVEL	Uncertain	0.32
Sift	Uncertain	0.0050	D;D;D
Sift4G	Uncertain	0.0060	D;D;D
Vest4		0.69
MutPred		0.66		Loss of stability (P = 0.0436);Loss of stability (P = 0.0436);Loss of stability (P = 0.0436);
MVP		0.91
MPC		1.3
ClinPred		0.96	D
GERP RS		5.4
gMVP		0.73

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: rs2069536599; hg19: chrX-113965870;