13-46834913-G-A

Position:

• chr13-46834913-G-A

Variant summary

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

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. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0017 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0024 (8 hom.)
• Consequence: HTR2A NM_000621.5 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.05

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 -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 id 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/exons	MANE	Protein	UniProt
HTR2A	NM_000621.5	c.1340C>T	p.Ala447Val	missense_variant	4/4	ENST00000542664.4	NP_000612.1
HTR2A	NM_001378924.1	c.1340C>T	p.Ala447Val	missense_variant	4/4		NP_001365853.1
HTR2A	NM_001165947.5	c.851C>T	p.Ala284Val	missense_variant	3/3		NP_001159419.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HTR2A	ENST00000542664.4	c.1340C>T	p.Ala447Val	missense_variant	4/4	1	NM_000621.5	ENSP00000437737	P1
HTR2A	ENST00000543956.5	c.851C>T	p.Ala284Val	missense_variant	3/3	1		ENSP00000441861

Frequencies

GnomAD3 genomes AF: 0.00169 AC: 257 AN: 152150 Hom.: 0 Cov.: 32

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

GnomAD3 exomes AF: 0.00153 AC: 383 AN: 251138 Hom.: 0 AF XY: 0.00162 AC XY: 220 AN XY: 135726

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 SAS exome AF: 0.000229

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.: 8 Cov.: 33 AF XY: 0.00227 AC XY: 1652 AN XY: 727174

Gnomad4 AFR exome AF: 0.000448

Gnomad4 AMR exome AF: 0.000850

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000174

Gnomad4 FIN exome AF: 0.000711

Gnomad4 NFE exome AF: 0.00289

Gnomad4 OTH exome AF: 0.00187

GnomAD4 genome AF: 0.00169 AC: 257 AN: 152268 Hom.: 0 Cov.: 32 AF XY: 0.00158 AC XY: 118 AN XY: 74456

Gnomad4 AFR AF: 0.000457

Gnomad4 AMR AF: 0.000981

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.000377

Gnomad4 NFE AF: 0.00281

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00219 Hom.: 3

Bravo AF: 0.00179

TwinsUK AF: 0.00297 AC: 11

ALSPAC AF: 0.00259 AC: 10

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00267 AC: 23

ExAC AF: 0.00148 AC: 180

Asia WGS AF: 0.000289 AC: 1 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

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 19, 2018	- -

HTR2A-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 12, 2020

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	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	18
DANN	Benign	0.92
DEOGEN2	Benign	0.093	T;T;.
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.32
FATHMM_MKL	Benign	0.54	D
LIST_S2	Benign	0.76	.;T;T
M_CAP	Benign	0.0070	T
MetaRNN	Benign	0.0040	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N;N;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.25	T
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	T
GERP RS		3.9
Varity_R		0.049
gMVP		0.30

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

LitVar

Other links and lift over

dbSNP: rs6308; hg19: chr13-47409048;