chrX-114726940-G-T

Variant names:

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

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_000868.4(HTR2C):​c.4G>T​(p.Val2Leu) 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 1,018,331 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 11/18 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 9.8e-7 (0 hom. 0 hem.)
• Consequence: HTR2C NM_000868.4 missense
• Clinical Significance: Not reported in ClinVar
• 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.370156).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HTR2C	NM_000868.4	c.4G>T	p.Val2Leu	missense_variant	Exon 3 of 6	ENST00000276198.6	NP_000859.2
HTR2C	NM_001256760.3	c.4G>T	p.Val2Leu	missense_variant	Exon 4 of 7		NP_001243689.2
HTR2C	NM_001256761.3	c.4G>T	p.Val2Leu	missense_variant	Exon 3 of 6		NP_001243690.2
LOC105373313	XR_001755943.2	n.728+3682C>A		intron_variant	Intron 4 of 4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HTR2C	ENST00000276198.6	c.4G>T	p.Val2Leu	missense_variant	Exon 3 of 6	1	NM_000868.4	ENSP00000276198.1
HTR2C	ENST00000371951.5	c.4G>T	p.Val2Leu	missense_variant	Exon 4 of 7	1		ENSP00000361019.1
HTR2C	ENST00000371950.3	c.4G>T	p.Val2Leu	missense_variant	Exon 3 of 6	1		ENSP00000361018.3

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 9.82e-7 AC: 1 AN: 1018331 Hom.: 0 Cov.: 21 AF XY: 0.00 AC XY: 0 AN XY: 315079

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000440

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.088	T
BayesDel_noAF	Benign	-0.36
CADD	Uncertain	24
DANN	Uncertain	1.0
FATHMM_MKL	Benign	0.70	D
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.37	T;T;T
MetaSVM	Benign	-1.0	T
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-0.50	N;N;N
REVEL	Benign	0.13
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Vest4		0.52
MutPred		0.20		Loss of methylation at R5 (P = 0.1631);Loss of methylation at R5 (P = 0.1631);Loss of methylation at R5 (P = 0.1631);
MVP		0.93
MPC		0.96
ClinPred		0.60	D
GERP RS		2.9
gMVP		0.30

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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;