X-114906591-G-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_000868.4(HTR2C):c.553G>A(p.Val185Ile) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000372 in 1,182,245 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 16 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/16 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000018 (0 hom., 1 hem., cov: 23)
  • Exomes 𝑓: 0.000039 (0 hom. 15 hem.)
• Consequence: HTR2C NM_000868.4 missense, splice_region
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.07

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

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.091353655).
• BS2: High Hemizygotes in GnomAdExome at 3 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HTR2C	NM_000868.4	c.553G>A	p.Val185Ile	missense_variant, splice_region_variant	6/6	ENST00000276198.6
HTR2C	NM_001256760.3	c.553G>A	p.Val185Ile	missense_variant, splice_region_variant	7/7
HTR2C	NM_001256761.3	c.458G>A	p.Cys153Tyr	missense_variant, splice_region_variant	6/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HTR2C	ENST00000276198.6	c.553G>A	p.Val185Ile	missense_variant, splice_region_variant	6/6	1	NM_000868.4	P1
HTR2C	ENST00000371951.5	c.553G>A	p.Val185Ile	missense_variant, splice_region_variant	7/7	1		P1
HTR2C	ENST00000371950.3	c.458G>A	p.Cys153Tyr	missense_variant, splice_region_variant	6/6	1

Frequencies

GnomAD3 genomes AF: 0.0000179 AC: 2 AN: 111694 Hom.: 0 Cov.: 23 AF XY: 0.0000295 AC XY: 1 AN XY: 33886

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000950

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000379

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000666 AC: 11 AN: 165109 Hom.: 0 AF XY: 0.0000560 AC XY: 3 AN XY: 53601

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000704

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000121

Gnomad OTH exome AF: 0.000250

GnomAD4 exome AF: 0.0000392 AC: 42 AN: 1070551 Hom.: 0 Cov.: 27 AF XY: 0.0000439 AC XY: 15 AN XY: 341433

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000592

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000352

Gnomad4 OTH exome AF: 0.000178

GnomAD4 genome AF: 0.0000179 AC: 2 AN: 111694 Hom.: 0 Cov.: 23 AF XY: 0.0000295 AC XY: 1 AN XY: 33886

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000950

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000379

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000508 Hom.: 2

Bravo AF: 0.00000756

ExAC AF: 0.0000742 AC: 9

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 27, 2023

The c.553G>A (p.V185I) alteration is located in exon 6 (coding exon 4) of the HTR2C gene. This alteration results from a G to A substitution at nucleotide position 553, causing the valine (V) at amino acid position 185 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.54
Cadd	Benign	15
Dann	Benign	0.24
FATHMM_MKL	Benign	0.68	D
M_CAP	Benign	0.0074	T
MetaRNN	Benign	0.091	T
MetaSVM	Benign	-0.96	T
MutationTaster	Benign	0.68	N;N;N
PROVEAN	Benign	7.9	N
REVEL	Benign	0.11
Sift	Benign	1.0	T
Sift4G	Benign	0.99	T
Vest4		0.29
MutPred		0.72		Loss of stability (P = 0.0618);
MVP		0.28
ClinPred		0.027	T
GERP RS		4.0

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: rs149710250; hg19: chrX-114141154;