X-114726956-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_000868.4(HTR2C):c.20C>T(p.Ala7Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000916 in 1,113,106 control chromosomes in the GnomAD database, including 1 homozygotes. There are 42 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict 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. A7A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000036 (0 hom., 2 hem., cov: 23)
  • Exomes 𝑓: 0.000098 (1 hom. 40 hem.)
• Consequence: HTR2C NM_000868.4 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.658

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.016252607).
• BP6: Variant X-114726956-C-T is Benign according to our data. Variant chrX-114726956-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 750988.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Hemizygotes in GnomAd at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HTR2C	NM_000868.4	c.20C>T	p.Ala7Val	missense_variant	3/6	ENST00000276198.6
LOC105373313	XR_001755943.2	n.728+3666G>A		intron_variant, non_coding_transcript_variant
HTR2C	NM_001256760.3	c.20C>T	p.Ala7Val	missense_variant	4/7
HTR2C	NM_001256761.3	c.20C>T	p.Ala7Val	missense_variant	3/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HTR2C	ENST00000276198.6	c.20C>T	p.Ala7Val	missense_variant	3/6	1	NM_000868.4	P1
HTR2C	ENST00000371951.5	c.20C>T	p.Ala7Val	missense_variant	4/7	1		P1
HTR2C	ENST00000371950.3	c.20C>T	p.Ala7Val	missense_variant	3/6	1

Frequencies

GnomAD3 genomes AF: 0.0000359 AC: 4 AN: 111559 Hom.: 0 Cov.: 23 AF XY: 0.0000593 AC XY: 2 AN XY: 33727

Gnomad AFR AF: 0.0000326

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000959

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000750

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000199 AC: 24 AN: 120756 Hom.: 0 AF XY: 0.000272 AC XY: 10 AN XY: 36708

Gnomad AFR exome AF: 0.000113

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00133

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000155

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000979 AC: 98 AN: 1001498 Hom.: 1 Cov.: 21 AF XY: 0.000132 AC XY: 40 AN XY: 303736

Gnomad4 AFR exome AF: 0.000278

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00117

Gnomad4 FIN exome AF: 0.0000252

Gnomad4 NFE exome AF: 0.0000407

Gnomad4 OTH exome AF: 0.000212

GnomAD4 genome AF: 0.0000358 AC: 4 AN: 111608 Hom.: 0 Cov.: 23 AF XY: 0.0000592 AC XY: 2 AN XY: 33786

Gnomad4 AFR AF: 0.0000325

Gnomad4 AMR AF: 0.0000958

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000752

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000491

ExAC AF: 0.000273 AC: 33

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

HTR2C-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 07, 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). -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Sep 07, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.72
Cadd	Benign	0.59
Dann	Uncertain	0.99
FATHMM_MKL	Benign	0.012	N
M_CAP	Benign	0.0092	T
MetaRNN	Benign	0.016	T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.66	N;N;N
REVEL	Benign	0.094
Sift	Benign	0.072	T;T;D
Sift4G	Pathogenic	0.0	D;D;D
Vest4		0.24
MVP		0.50
MPC		0.37
ClinPred		0.044	T
GERP RS		-0.42
gMVP		0.56

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs201115463; hg19: chrX-113961365; COSMIC: COSV52202941;