rs193920954

Variant names:

• chrX-114848155-C-T
• rs193920954
• NM_000868.4:c.502C>T

Variant summary

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

The NM_000868.4(HTR2C):​c.502C>T​(p.Arg168Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency: Genomes: not found (cov: 23)
• Consequence: HTR2C NM_000868.4 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 3.03

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]

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 rank	MANE	Protein	UniProt
HTR2C	NM_000868.4	c.502C>T	p.Arg168Trp	missense_variant	Exon 5 of 6	ENST00000276198.6	NP_000859.2
HTR2C	NM_001256760.3	c.502C>T	p.Arg168Trp	missense_variant	Exon 6 of 7		NP_001243689.2
HTR2C	NM_001256761.3	c.455+47C>T		intron_variant	Intron 5 of 5		NP_001243690.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HTR2C	ENST00000276198.6	c.502C>T	p.Arg168Trp	missense_variant	Exon 5 of 6	1	NM_000868.4	ENSP00000276198.1
HTR2C	ENST00000371951.5	c.502C>T	p.Arg168Trp	missense_variant	Exon 6 of 7	1		ENSP00000361019.1
HTR2C	ENST00000371950.3	c.455+47C>T		intron_variant	Intron 5 of 5	1		ENSP00000361018.3

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 23

EpiCase AF: 0.0000549

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

Malignant tumor of prostate Uncertain:1

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Science for Life laboratory, Karolinska Institutet

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.55
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Pathogenic	27
DANN	Pathogenic	1.0
FATHMM_MKL	Uncertain	0.88	D
M_CAP	Uncertain	0.15	D
MetaRNN	Uncertain	0.66	D;D
MetaSVM	Uncertain	-0.0021	T
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-4.7	D;D
REVEL	Pathogenic	0.72
Sift	Uncertain	0.027	D;D
Sift4G	Uncertain	0.021	D;D
Vest4		0.56
MutPred		0.70		Loss of disorder (P = 0.0056);Loss of disorder (P = 0.0056);
MVP		0.72
MPC		0.82
ClinPred		0.99	D
GERP RS		4.3
gMVP		0.88

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs193920954; hg19: chrX-114082718; COSMIC: COSV52214562;