rs6308

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_000621.5(HTR2A):c.1340C>T(p.Ala447Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00229 in 1,614,018 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A447T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0017 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0024 ( 8 hom. )

Consequence

HTR2A
NM_000621.5 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 2.05

Publications

23 publications found

Variant links:

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]

HTR2A links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0039823055).

BP6

Variant 13-46834913-G-A is Benign according to our data. Variant chr13-46834913-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 778992.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAd4 at 257 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
HTR2A	NM_000621.5 link	c.1340C>T	p.Ala447Val	missense_variant	Exon 4 of 4	ENST00000542664.4	NP_000612.1
HTR2A	NM_001378924.1 link	c.1340C>T	p.Ala447Val	missense_variant	Exon 4 of 4		NP_001365853.1
HTR2A	NM_001165947.5 link	c.851C>T	p.Ala284Val	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 link	c.1340C>T	p.Ala447Val	missense_variant	Exon 4 of 4	1	NM_000621.5	ENSP00000437737.1
HTR2A	ENST00000543956.5 link	c.851C>T	p.Ala284Val	missense_variant	Exon 3 of 3	1		ENSP00000441861.2

Frequencies

GnomAD3 genomes

AF:

0.00169

AC:

257

AN:

152150

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000459

Gnomad AMI

AF:

0.0230

Gnomad AMR

AF:

0.000982

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.000377

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00281

Gnomad OTH

AF:

0.00287

GnomAD2 exomes

AF:

0.00153

AC:

383

AN:

251138

AF XY:

0.00162

show subpopulations

Gnomad AFR exome

AF:

0.000431

Gnomad AMR exome

AF:

0.000897

Gnomad ASJ exome

AF:

0.0000993

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000693

Gnomad NFE exome

AF:

0.00274

Gnomad OTH exome

AF:

0.00180

GnomAD4 exome

AF:

0.00235

AC:

3437

AN:

1461750

Hom.:

Cov.:

AF XY:

0.00227

AC XY:

1652

AN XY:

727174

show subpopulations

African (AFR)

AF:

0.000448

AC:

AN:

33462

American (AMR)

AF:

0.000850

AC:

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.000174

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.000711

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.000520

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00289

AC:

3214

AN:

1111918

Other (OTH)

AF:

0.00187

AC:

113

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

177

354

530

707

884

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

126

252

378

504

630

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00169

AC:

257

AN:

152268

Hom.:

Cov.:

AF XY:

0.00158

AC XY:

118

AN XY:

74456

show subpopulations

African (AFR)

AF:

0.000457

AC:

AN:

41558

American (AMR)

AF:

0.000981

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.000207

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.000377

AC:

AN:

10604

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00281

AC:

191

AN:

68012

Other (OTH)

AF:

0.00284

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00209

Hom.:

Bravo

AF:

0.00179

TwinsUK

AF:

0.00297

AC:

ALSPAC

AF:

0.00259

AC:

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.00267

AC:

ExAC

AF:

0.00148

AC:

180

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00213

EpiControl

AF:

0.00290

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Jul 19, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

HTR2A-related disorder

Benign:1

May 12, 2020

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.074

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.57

CADD

Benign

(source)

DANN

Benign

0.92

DEOGEN2

Benign

0.093

T;T;.

Eigen

Benign

-0.45

Eigen_PC

Benign

-0.32

FATHMM_MKL

Benign

0.54

LIST_S2

Benign

0.76

.;T;T

M_CAP

Benign

0.0070

MetaRNN

Benign

0.0040

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.0

N;N;.

PhyloP100

2.1

PrimateAI

Benign

0.25

PROVEAN

Benign

-0.070

N;N;N

REVEL

Benign

0.12

Sift

Benign

0.30

T;T;T

Sift4G

Benign

0.31

T;T;T

Polyphen

0.0

B;B;.

Vest4

0.054

MVP

0.53

MPC

0.27

ClinPred

0.0037

GERP RS

3.9

Varity_R

0.049

gMVP

0.30

Mutation Taster

=85/15

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over