X-114589605-A-G

Variant names:

• chrX-114589605-A-G
• rs17260565
• NM_000868.4:c.-147+4946A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000868.4(HTR2C):​c.-147+4946A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.138 in 166,969 control chromosomes in the GnomAD database, including 1,323 homozygotes. There are 6,733 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.13 (759 hom., 4205 hem., cov: 23)
  • Exomes 𝑓: 0.16 (564 hom. 2528 hem.)
• Consequence: HTR2C NM_000868.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.410
• Publications: 4 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]

RPL36AP53 (HGNC:36517): (ribosomal protein L36a pseudogene 53)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• 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.-147+4946A>G		intron	N/A	NP_000859.2
	HTR2C	NM_001256760.3		c.-238+4946A>G		intron	N/A	NP_001243689.2
	HTR2C	NM_001256761.3		c.-147+4946A>G		intron	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.-147+4946A>G		intron	N/A	ENSP00000276198.1
	HTR2C	ENST00000371951.5	TSL:1	c.-238+4946A>G		intron	N/A	ENSP00000361019.1
	HTR2C	ENST00000371950.3	TSL:1	c.-147+4946A>G		intron	N/A	ENSP00000361018.3

Frequencies

GnomAD3 genomes AF: 0.126 AC: 14012 AN: 110905 Hom.: 760 Cov.: 23

Gnomad AFR AF: 0.0293

Gnomad AMI AF: 0.0292

Gnomad AMR AF: 0.141

Gnomad ASJ AF: 0.144

Gnomad EAS AF: 0.130

Gnomad SAS AF: 0.270

Gnomad FIN AF: 0.148

Gnomad MID AF: 0.114

Gnomad NFE AF: 0.170

Gnomad OTH AF: 0.126

GnomAD4 exome AF: 0.162 AC: 9056 AN: 56009 Hom.: 564 Cov.: 0 AF XY: 0.168 AC XY: 2528 AN XY: 15085

African (AFR) AF: 0.0228 AC: 34 AN: 1494

American (AMR) AF: 0.149 AC: 894 AN: 6000

Ashkenazi Jewish (ASJ) AF: 0.124 AC: 144 AN: 1157

East Asian (EAS) AF: 0.114 AC: 330 AN: 2905

South Asian (SAS) AF: 0.263 AC: 1384 AN: 5253

European-Finnish (FIN) AF: 0.150 AC: 535 AN: 3576

Middle Eastern (MID) AF: 0.130 AC: 20 AN: 154

European-Non Finnish (NFE) AF: 0.160 AC: 5224 AN: 32629

Other (OTH) AF: 0.173 AC: 491 AN: 2841

GnomAD4 genome AF: 0.126 AC: 14017 AN: 110960 Hom.: 759 Cov.: 23 AF XY: 0.127 AC XY: 4205 AN XY: 33168

African (AFR) AF: 0.0294 AC: 901 AN: 30674

American (AMR) AF: 0.141 AC: 1463 AN: 10345

Ashkenazi Jewish (ASJ) AF: 0.144 AC: 381 AN: 2650

East Asian (EAS) AF: 0.131 AC: 454 AN: 3472

South Asian (SAS) AF: 0.270 AC: 695 AN: 2573

European-Finnish (FIN) AF: 0.148 AC: 881 AN: 5937

Middle Eastern (MID) AF: 0.111 AC: 24 AN: 216

European-Non Finnish (NFE) AF: 0.170 AC: 9010 AN: 52915

Other (OTH) AF: 0.126 AC: 188 AN: 1494

Alfa AF: 0.148 Hom.: 859

Bravo AF: 0.119

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	4.2
DANN	Benign	0.64
PhyloP100		-0.41
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs17260565; hg19: chrX-113824073;