X-114731382-G-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_000868.4(HTR2C):c.124G>C(p.Asp42His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00015 in 1,202,185 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 51 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00074 (0 hom., 23 hem., cov: 22)
  • Exomes 𝑓: 0.000090 (0 hom. 28 hem.)
• Consequence: HTR2C NM_000868.4 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.41

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 Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010652423).
• BP6: Variant X-114731382-G-C is Benign according to our data. Variant chrX-114731382-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 738592.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Hemizygotes in GnomAd at 23 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HTR2C	NM_000868.4	c.124G>C	p.Asp42His	missense_variant	4/6	ENST00000276198.6
LOC105373313	XR_001755943.2	n.574-606C>G		intron_variant, non_coding_transcript_variant
HTR2C	NM_001256760.3	c.124G>C	p.Asp42His	missense_variant	5/7
HTR2C	NM_001256761.3	c.124G>C	p.Asp42His	missense_variant	4/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HTR2C	ENST00000276198.6	c.124G>C	p.Asp42His	missense_variant	4/6	1	NM_000868.4	P1
HTR2C	ENST00000371951.5	c.124G>C	p.Asp42His	missense_variant	5/7	1		P1
HTR2C	ENST00000371950.3	c.124G>C	p.Asp42His	missense_variant	4/6	1

Frequencies

GnomAD3 genomes AF: 0.000742 AC: 82 AN: 110499 Hom.: 0 Cov.: 22 AF XY: 0.000702 AC XY: 23 AN XY: 32781

Gnomad AFR AF: 0.00254

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000292

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: 0.00135

GnomAD3 exomes AF: 0.000229 AC: 42 AN: 183396 Hom.: 0 AF XY: 0.000162 AC XY: 11 AN XY: 67838

Gnomad AFR exome AF: 0.00304

Gnomad AMR exome AF: 0.0000730

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: 0.0000898 AC: 98 AN: 1091641 Hom.: 0 Cov.: 30 AF XY: 0.0000784 AC XY: 28 AN XY: 357139

Gnomad4 AFR exome AF: 0.00358

Gnomad4 AMR exome AF: 0.0000852

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: 0.00000120

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.000742 AC: 82 AN: 110544 Hom.: 0 Cov.: 22 AF XY: 0.000700 AC XY: 23 AN XY: 32836

Gnomad4 AFR AF: 0.00253

Gnomad4 AMR AF: 0.000292

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: 0.00134

Alfa AF: 0.0000678 Hom.: 1

Bravo AF: 0.000774

ESP6500AA AF: 0.00209 AC: 8

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000247 AC: 30

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

HTR2C-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 13, 2021

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). -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Oct 10, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.35
Cadd	Benign	17
Dann	Uncertain	0.99
FATHMM_MKL	Uncertain	0.94	D
M_CAP	Uncertain	0.16	D
MetaRNN	Benign	0.011	T;T;T
MetaSVM	Benign	-0.98	T
MutationTaster	Benign	0.91	N;N;N
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.57	N;N;N
REVEL	Benign	0.20
Sift	Benign	0.073	T;T;D
Sift4G	Uncertain	0.059	T;T;D
Vest4		0.11
MVP		0.64
MPC		0.44
ClinPred		0.048	T
GERP RS		3.3
gMVP		0.31

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: rs143566182; hg19: chrX-113965791;