rs1058576

Positions:

• chr13-46834991-G-A
• chr13-46834991-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_000621.5(HTR2A):​c.1262C>T​(p.Ser421Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: HTR2A NM_000621.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.51

Genes affected

HTR2A (HGNC:5293): (5-hydroxytryptamine receptor 2A) This gene encodes one of the receptors for serotonin, a neurotransmitter with many roles. Mutations in this gene are associated with susceptibility to schizophrenia and obsessive-compulsive disorder, and are also associated with response to the antidepressant citalopram in patients with major depressive disorder (MDD). MDD patients who also have a mutation in intron 2 of this gene show a significantly reduced response to citalopram as this antidepressant downregulates expression of this gene. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2009]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HTR2A	NM_000621.5	c.1262C>T	p.Ser421Phe	missense_variant	4/4	ENST00000542664.4	NP_000612.1
HTR2A	NM_001378924.1	c.1262C>T	p.Ser421Phe	missense_variant	4/4		NP_001365853.1
HTR2A	NM_001165947.5	c.773C>T	p.Ser258Phe	missense_variant	3/3		NP_001159419.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HTR2A	ENST00000542664.4	c.1262C>T	p.Ser421Phe	missense_variant	4/4	1	NM_000621.5	ENSP00000437737.1
HTR2A	ENST00000543956.5	c.773C>T	p.Ser258Phe	missense_variant	3/3	1		ENSP00000441861.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.40
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.65	D;D;.
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.94	.;D;D
M_CAP	Benign	0.038	D
MetaRNN	Uncertain	0.72	D;D;D
MetaSVM	Benign	-0.52	T
MutationAssessor	Benign	0.97	L;L;.
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-2.9	D;D;D
REVEL	Uncertain	0.35
Sift	Uncertain	0.0090	D;D;D
Sift4G	Uncertain	0.015	D;D;D
Polyphen		0.99	D;D;.
Vest4		0.71
MutPred		0.45		Loss of disorder (P = 0.0048);Loss of disorder (P = 0.0048);.;
MVP		0.80
MPC		0.99
ClinPred		0.99	D
GERP RS		5.7
Varity_R		0.46
gMVP		0.63

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: rs1058576; hg19: chr13-47409126;