rs782483805

Variant names:

• chrX-114731301-C-T
• rs782483805
• NM_000868.4:c.43C>T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Moderate BP6 BP7 BS2

The NM_000868.4(HTR2C):​c.43C>T​(p.Leu15Leu) 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 (no stars). 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 no assertion criteria provided B:1
• Conservation: PhyloP100: 3.25
• Publications: 0 publications found

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]

ENSG00000306059 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -8 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 VariationId is 3047470.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP7: Synonymous conserved (PhyloP=3.24 with no splicing effect.
• BS2: High Hemizygotes in GnomAd4 at 4 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000868.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HTR2C	NM_000868.4	MANE Select	c.43C>T	p.Leu15Leu	synonymous	Exon 4 of 6	NP_000859.2	P28335-1
	HTR2C	NM_001256760.3		c.43C>T	p.Leu15Leu	synonymous	Exon 5 of 7	NP_001243689.2	P28335-1
	HTR2C	NM_001256761.3		c.43C>T	p.Leu15Leu	synonymous	Exon 4 of 6	NP_001243690.2	P28335-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HTR2C	ENST00000276198.6	TSL:1 MANE Select	c.43C>T	p.Leu15Leu	synonymous	Exon 4 of 6	ENSP00000276198.1	P28335-1
	HTR2C	ENST00000371951.5	TSL:1	c.43C>T	p.Leu15Leu	synonymous	Exon 5 of 7	ENSP00000361019.1	P28335-1
	HTR2C	ENST00000371950.3	TSL:1	c.43C>T	p.Leu15Leu	synonymous	Exon 4 of 6	ENSP00000361018.3	P28335-2

Frequencies

GnomAD3 genomes AF: 0.000100 AC: 11 AN: 109716 Hom.: 0 Cov.: 23

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

GnomAD2 exomes AF: 0.0000177 AC: 3 AN: 169476 AF XY: 0.0000175

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 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

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 25327

American (AMR) AF: 0.0000610 AC: 2 AN: 32765

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18597

East Asian (EAS) AF: 0.00 AC: 0 AN: 29904

South Asian (SAS) AF: 0.00 AC: 0 AN: 51282

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40258

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4001

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 823211

Other (OTH) AF: 0.0000445 AC: 2 AN: 44961

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0448430), which strongly suggests a high chance of mosaicism in these individuals.

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

African (AFR) AF: 0.000332 AC: 10 AN: 30087

American (AMR) AF: 0.0000977 AC: 1 AN: 10236

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2634

East Asian (EAS) AF: 0.00 AC: 0 AN: 3514

South Asian (SAS) AF: 0.00 AC: 0 AN: 2578

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5572

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 233

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 52702

Other (OTH) AF: 0.00 AC: 0 AN: 1473

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000567

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	HTR2C-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.39
CADD	Benign	9.2
DANN	Benign	0.79
PhyloP100		3.2
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs782483805; hg19: chrX-113965710;