rs6314

Variant names:

• chr13-46834899-G-A
• rs6314
• NM_000621.5:c.1354C>T

Variant summary

Our verdict is Benign. The variant received -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. 16/21 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 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
• Publications: 257 publications found

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

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
HTR2A	NM_000621.5	c.1354C>T	p.His452Tyr	missense_variant	Exon 4 of 4	ENST00000542664.4	NP_000612.1
HTR2A	NM_001378924.1	c.1354C>T	p.His452Tyr	missense_variant	Exon 4 of 4		NP_001365853.1
HTR2A	NM_001165947.5	c.865C>T	p.His289Tyr	missense_variant	Exon 3 of 3		NP_001159419.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HTR2A	ENST00000542664.4	c.1354C>T	p.His452Tyr	missense_variant	Exon 4 of 4	1	NM_000621.5	ENSP00000437737.1
HTR2A	ENST00000543956.5	c.865C>T	p.His289Tyr	missense_variant	Exon 3 of 3	1		ENSP00000441861.2

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

GnomAD2 exomes AF: 0.0786 AC: 19741 AN: 251056 AF XY: 0.0804

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 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

African (AFR) AF: 0.131 AC: 4381 AN: 33458

American (AMR) AF: 0.0549 AC: 2454 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.128 AC: 3334 AN: 26128

East Asian (EAS) AF: 0.000579 AC: 23 AN: 39696

South Asian (SAS) AF: 0.0957 AC: 8251 AN: 86248

European-Finnish (FIN) AF: 0.0454 AC: 2423 AN: 53402

Middle Eastern (MID) AF: 0.108 AC: 621 AN: 5766

European-Non Finnish (NFE) AF: 0.0896 AC: 99579 AN: 1111582

Other (OTH) AF: 0.0908 AC: 5482 AN: 60376

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

African (AFR) AF: 0.125 AC: 5185 AN: 41526

American (AMR) AF: 0.0755 AC: 1155 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.133 AC: 460 AN: 3470

East Asian (EAS) AF: 0.00251 AC: 13 AN: 5178

South Asian (SAS) AF: 0.0919 AC: 443 AN: 4818

European-Finnish (FIN) AF: 0.0527 AC: 558 AN: 10582

Middle Eastern (MID) AF: 0.0986 AC: 29 AN: 294

European-Non Finnish (NFE) AF: 0.0898 AC: 6107 AN: 67988

Other (OTH) AF: 0.0949 AC: 200 AN: 2108

Alfa AF: 0.0913 Hom.: 2472

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
LIST_S2	Benign	0.68	.;T;T
MetaRNN	Benign	0.0016	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.55	N;N;.
PhyloP100		0.89
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
Mutation Taster		=96/4	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: rs6314; hg19: chr13-47409034; COSMIC: COSV66327120;