X-114584047-C-T

Variant names:

• chrX-114584047-C-T
• rs3813929
• NM_000868.4:c.-759C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000868.4(HTR2C):​c.-759C>T variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.127 in 111,327 control chromosomes in the GnomAD database, including 762 homozygotes. There are 4,306 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (761 hom., 4286 hem., cov: 21)
  • Exomes 𝑓: 0.16 (1 hom. 20 hem.)
• Consequence: HTR2C NM_000868.4 upstream_gene
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.695
• Publications: 220 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]

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).
• BP6: Variant X-114584047-C-T is Benign according to our data. Variant chrX-114584047-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 225992.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.253 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HTR2C	NM_000868.4	MANE Select	c.-759C>T		upstream_gene	N/A	NP_000859.2
	HTR2C	NM_001256760.3		c.-850C>T		upstream_gene	N/A	NP_001243689.2
	HTR2C	NM_001256761.3		c.-759C>T		upstream_gene	N/A	NP_001243690.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HTR2C	ENST00000276198.6	TSL:1 MANE Select	c.-759C>T		upstream_gene	N/A	ENSP00000276198.1
	HTR2C	ENST00000371951.5	TSL:1	c.-850C>T		upstream_gene	N/A	ENSP00000361019.1
	HTR2C	ENST00000371950.3	TSL:1	c.-759C>T		upstream_gene	N/A	ENSP00000361018.3

Frequencies

GnomAD3 genomes AF: 0.127 AC: 14111 AN: 110991 Hom.: 762 Cov.: 21

Gnomad AFR AF: 0.0298

Gnomad AMI AF: 0.0294

Gnomad AMR AF: 0.143

Gnomad ASJ AF: 0.146

Gnomad EAS AF: 0.132

Gnomad SAS AF: 0.270

Gnomad FIN AF: 0.149

Gnomad MID AF: 0.120

Gnomad NFE AF: 0.171

Gnomad OTH AF: 0.128

GnomAD4 exome AF: 0.155 AC: 44 AN: 283 Hom.: 1 Cov.: 0 AF XY: 0.180 AC XY: 20 AN XY: 111

African (AFR) AF: 0.00 AC: 0 AN: 2

American (AMR) AF: 0.00 AC: 0 AN: 1

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.151 AC: 32 AN: 212

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.188 AC: 12 AN: 64

Other (OTH) AF: 0.00 AC: 0 AN: 4

GnomAD4 genome AF: 0.127 AC: 14116 AN: 111044 Hom.: 761 Cov.: 21 AF XY: 0.129 AC XY: 4286 AN XY: 33278

African (AFR) AF: 0.0299 AC: 917 AN: 30714

American (AMR) AF: 0.143 AC: 1506 AN: 10503

Ashkenazi Jewish (ASJ) AF: 0.146 AC: 386 AN: 2641

East Asian (EAS) AF: 0.132 AC: 453 AN: 3432

South Asian (SAS) AF: 0.269 AC: 698 AN: 2590

European-Finnish (FIN) AF: 0.149 AC: 884 AN: 5932

Middle Eastern (MID) AF: 0.117 AC: 25 AN: 213

European-Non Finnish (NFE) AF: 0.171 AC: 9033 AN: 52824

Other (OTH) AF: 0.128 AC: 194 AN: 1515

Alfa AF: 0.134 Hom.: 6651

Bravo AF: 0.119

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	4.0
DANN	Benign	0.93
PhyloP100		-0.69
PromoterAI		0.11	Neutral

Splicing

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

Other links and lift over

dbSNP: rs3813929; hg19: chrX-113818520; COSMIC: COSV52200938;