chrX-114848083-C-A

Position:

• chrX-114848083-C-A

Variant summary

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

The NM_000868.4(HTR2C):​c.430C>A​(p.His144Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 24)
• Consequence: HTR2C NM_000868.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.77

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/exons	MANE	UniProt
HTR2C	NM_000868.4	c.430C>A	p.His144Asn	missense_variant	5/6	ENST00000276198.6
HTR2C	NM_001256760.3	c.430C>A	p.His144Asn	missense_variant	6/7
HTR2C	NM_001256761.3	c.430C>A	p.His144Asn	missense_variant	5/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HTR2C	ENST00000276198.6	c.430C>A	p.His144Asn	missense_variant	5/6	1	NM_000868.4	P1
HTR2C	ENST00000371951.5	c.430C>A	p.His144Asn	missense_variant	6/7	1		P1
HTR2C	ENST00000371950.3	c.430C>A	p.His144Asn	missense_variant	5/6	1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 24

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

Oct 17, 2023

The c.430C>A (p.H144N) alteration is located in exon 5 (coding exon 3) of the HTR2C gene. This alteration results from a C to A substitution at nucleotide position 430, causing the histidine (H) at amino acid position 144 to be replaced by an asparagine (N). 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	Pathogenic	0.95
BayesDel_addAF	Benign	-0.049	T
BayesDel_noAF	Benign	-0.31
CADD	Pathogenic	27
DANN	Uncertain	0.99
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Benign	0.041	D
MetaRNN	Uncertain	0.69	D;D;D
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-5.8	D;D;D
REVEL	Benign	0.27
Sift	Pathogenic	0.0	D;D;T
Sift4G	Benign	0.21	T;T;T
Vest4		0.77
MutPred		0.70		Loss of catalytic residue at I142 (P = 0.1132);Loss of catalytic residue at I142 (P = 0.1132);Loss of catalytic residue at I142 (P = 0.1132);
MVP		0.66
MPC		1.2
ClinPred		1.0	D
GERP RS		4.4
gMVP		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-114082646;