rs6314

Positions:

• chr13-46834899-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000621.5(HTR2A):​c.1354C>T​(p.His452Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0872 in 1,613,530 control chromosomes in the GnomAD database, including 6,772 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H452P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.093 (721 hom., cov: 32)
  • Exomes 𝑓: 0.087 (6051 hom.)
• Consequence: HTR2A NM_000621.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.891

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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0016472638).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.122 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HTR2A	NM_000621.5	c.1354C>T	p.His452Tyr	missense_variant	4/4	ENST00000542664.4
HTR2A	NM_001378924.1	c.1354C>T	p.His452Tyr	missense_variant	4/4
HTR2A	NM_001165947.5	c.865C>T	p.His289Tyr	missense_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HTR2A	ENST00000542664.4	c.1354C>T	p.His452Tyr	missense_variant	4/4	1	NM_000621.5	P1
HTR2A	ENST00000543956.5	c.865C>T	p.His289Tyr	missense_variant	3/3	1

Frequencies

GnomAD3 genomes AF: 0.0931 AC: 14163 AN: 152046 Hom.: 717 Cov.: 32

Gnomad AFR AF: 0.125

Gnomad AMI AF: 0.0351

Gnomad AMR AF: 0.0756

Gnomad ASJ AF: 0.133

Gnomad EAS AF: 0.00270

Gnomad SAS AF: 0.0912

Gnomad FIN AF: 0.0527

Gnomad MID AF: 0.0981

Gnomad NFE AF: 0.0898

Gnomad OTH AF: 0.0954

GnomAD3 exomes AF: 0.0786 AC: 19741 AN: 251056 Hom.: 911 AF XY: 0.0804 AC XY: 10909 AN XY: 135674

Gnomad AFR exome AF: 0.130

Gnomad AMR exome AF: 0.0537

Gnomad ASJ exome AF: 0.130

Gnomad EAS exome AF: 0.000979

Gnomad SAS exome AF: 0.0939

Gnomad FIN exome AF: 0.0473

Gnomad NFE exome AF: 0.0887

Gnomad OTH exome AF: 0.0780

GnomAD4 exome AF: 0.0866 AC: 126548 AN: 1461366 Hom.: 6051 Cov.: 33 AF XY: 0.0874 AC XY: 63528 AN XY: 727010

Gnomad4 AFR exome AF: 0.131

Gnomad4 AMR exome AF: 0.0549

Gnomad4 ASJ exome AF: 0.128

Gnomad4 EAS exome AF: 0.000579

Gnomad4 SAS exome AF: 0.0957

Gnomad4 FIN exome AF: 0.0454

Gnomad4 NFE exome AF: 0.0896

Gnomad4 OTH exome AF: 0.0908

GnomAD4 genome AF: 0.0932 AC: 14182 AN: 152164 Hom.: 721 Cov.: 32 AF XY: 0.0913 AC XY: 6788 AN XY: 74386

Gnomad4 AFR AF: 0.125

Gnomad4 AMR AF: 0.0755

Gnomad4 ASJ AF: 0.133

Gnomad4 EAS AF: 0.00251

Gnomad4 SAS AF: 0.0919

Gnomad4 FIN AF: 0.0527

Gnomad4 NFE AF: 0.0898

Gnomad4 OTH AF: 0.0949

Alfa AF: 0.0920 Hom.: 1185

Bravo AF: 0.0951

TwinsUK AF: 0.0885 AC: 328

ALSPAC AF: 0.0929 AC: 358

ESP6500AA AF: 0.133 AC: 588

ESP6500EA AF: 0.0926 AC: 796

ExAC AF: 0.0789 AC: 9578

Asia WGS AF: 0.0480 AC: 170 AN: 3478

EpiCase AF: 0.0980

EpiControl AF: 0.100

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	5.4
DANN	Benign	0.89
DEOGEN2	Benign	0.19	T;T;.
Eigen	Benign	-0.66
Eigen_PC	Benign	-0.73
FATHMM_MKL	Benign	0.17	N
MetaRNN	Benign	0.0016	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.55	N;N;.
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-1.5	N;N;N
REVEL	Benign	0.074
Sift	Benign	0.068	T;T;D
Sift4G	Benign	0.11	T;T;D
Polyphen		0.010	B;B;.
Vest4		0.057
MPC		0.33
ClinPred		0.0098	T
GERP RS		1.7
Varity_R		0.064
gMVP		0.23

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: rs6314; hg19: chr13-47409034; COSMIC: COSV66327120;