X-114906816-A-G

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_000868.4(HTR2C):c.778A>G(p.Ser260Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000902 in 1,208,748 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 29 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00045 (0 hom., 15 hem., cov: 22)
  • Exomes 𝑓: 0.000054 (0 hom. 14 hem.)
• Consequence: HTR2C NM_000868.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0840

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 Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006207794).
• BP6: Variant X-114906816-A-G is Benign according to our data. Variant chrX-114906816-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 3059916.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Hemizygotes in GnomAd at 15 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HTR2C	NM_000868.4	c.778A>G	p.Ser260Gly	missense_variant	6/6	ENST00000276198.6
HTR2C	NM_001256760.3	c.778A>G	p.Ser260Gly	missense_variant	7/7
HTR2C	NM_001256761.3	c.683A>G	p.Lys228Arg	missense_variant	6/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HTR2C	ENST00000276198.6	c.778A>G	p.Ser260Gly	missense_variant	6/6	1	NM_000868.4	P1
HTR2C	ENST00000371951.5	c.778A>G	p.Ser260Gly	missense_variant	7/7	1		P1
HTR2C	ENST00000371950.3	c.683A>G	p.Lys228Arg	missense_variant	6/6	1

Frequencies

GnomAD3 genomes AF: 0.000452 AC: 50 AN: 110617 Hom.: 0 Cov.: 22 AF XY: 0.000457 AC XY: 15 AN XY: 32821

Gnomad AFR AF: 0.00161

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000670

GnomAD3 exomes AF: 0.000147 AC: 27 AN: 183211 Hom.: 0 AF XY: 0.0000738 AC XY: 5 AN XY: 67761

Gnomad AFR exome AF: 0.00190

Gnomad AMR exome AF: 0.0000729

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000537 AC: 59 AN: 1098075 Hom.: 0 Cov.: 31 AF XY: 0.0000385 AC XY: 14 AN XY: 363443

Gnomad4 AFR exome AF: 0.00167

Gnomad4 AMR exome AF: 0.000114

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: 0.00000238

Gnomad4 OTH exome AF: 0.000195

GnomAD4 genome AF: 0.000452 AC: 50 AN: 110673 Hom.: 0 Cov.: 22 AF XY: 0.000456 AC XY: 15 AN XY: 32887

Gnomad4 AFR AF: 0.00161

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000661

Alfa AF: 0.0000107 Hom.: 0

Bravo AF: 0.000642

ESP6500AA AF: 0.000782 AC: 3

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000165 AC: 20

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

HTR2C-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 09, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.54
Cadd	Benign	12
Dann	Benign	0.96
FATHMM_MKL	Benign	0.056	N
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.0062	T
MetaSVM	Benign	-0.99	T
MutationTaster	Benign	1.0	N;N;N
PROVEAN	Benign	-0.41	N
REVEL	Benign	0.078
Sift	Pathogenic	0.0	D
Vest4		0.17
MVP		0.19
ClinPred		0.015	T
GERP RS		0.24

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: rs148470204; hg19: chrX-114141379; COSMIC: COSV52207732;