X-114731301-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Moderate BP6_Moderate BP7 BS2

The NM_000868.4(HTR2C):c.43C>T(p.Leu15=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000127 in 1,180,022 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 6 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Synonymous variant affecting the same amino acid position (i.e. L15L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00010 (0 hom., 4 hem., cov: 23)
  • Exomes 𝑓: 0.0000037 (0 hom. 2 hem.)
• Consequence: HTR2C NM_000868.4 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.25

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.39).
• BP6: Variant X-114731301-C-T is Benign according to our data. Variant chrX-114731301-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 3047470.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=3.24 with no splicing effect.
• BS2: High Hemizygotes in GnomAd at 4 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HTR2C	NM_000868.4	c.43C>T	p.Leu15=	synonymous_variant	4/6	ENST00000276198.6
LOC105373313	XR_001755943.2	n.574-525G>A		intron_variant, non_coding_transcript_variant
HTR2C	NM_001256760.3	c.43C>T	p.Leu15=	synonymous_variant	5/7
HTR2C	NM_001256761.3	c.43C>T	p.Leu15=	synonymous_variant	4/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HTR2C	ENST00000276198.6	c.43C>T	p.Leu15=	synonymous_variant	4/6	1	NM_000868.4	P1
HTR2C	ENST00000371951.5	c.43C>T	p.Leu15=	synonymous_variant	5/7	1		P1
HTR2C	ENST00000371950.3	c.43C>T	p.Leu15=	synonymous_variant	4/6	1

Frequencies

GnomAD3 genomes AF: 0.000100 AC: 11 AN: 109716 Hom.: 0 Cov.: 23 AF XY: 0.000124 AC XY: 4 AN XY: 32170

Gnomad AFR AF: 0.000332

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000977

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: 0.00

GnomAD3 exomes AF: 0.0000177 AC: 3 AN: 169476 Hom.: 0 AF XY: 0.0000175 AC XY: 1 AN XY: 57226

Gnomad AFR exome AF: 0.0000772

Gnomad AMR exome AF: 0.0000405

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: 0.000244

GnomAD4 exome AF: 0.00000374 AC: 4 AN: 1070306 Hom.: 0 Cov.: 27 AF XY: 0.00000586 AC XY: 2 AN XY: 341316

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000610

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: 0.0000445

GnomAD4 genome AF: 0.000100 AC: 11 AN: 109716 Hom.: 0 Cov.: 23 AF XY: 0.000124 AC XY: 4 AN XY: 32170

Gnomad4 AFR AF: 0.000332

Gnomad4 AMR AF: 0.0000977

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: 0.00

Bravo AF: 0.0000567

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

Nov 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
BayesDel_noAF	Benign	-0.39
Cadd	Benign	9.2
Dann	Benign	0.79

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: rs782483805; hg19: chrX-113965710;