13-46834898-T-G

Position:

• chr13-46834898-T-G

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_000621.5(HTR2A):​c.1355A>C​(p.His452Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000609 in 1,461,762 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H452Y) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000061 (0 hom.)
• Consequence: HTR2A NM_000621.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.309

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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.04908693).
• BS2: High AC in GnomAdExome4 at 89 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HTR2A	NM_000621.5	c.1355A>C	p.His452Pro	missense_variant	4/4	ENST00000542664.4	NP_000612.1
HTR2A	NM_001378924.1	c.1355A>C	p.His452Pro	missense_variant	4/4		NP_001365853.1
HTR2A	NM_001165947.5	c.866A>C	p.His289Pro	missense_variant	3/3		NP_001159419.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HTR2A	ENST00000542664.4	c.1355A>C	p.His452Pro	missense_variant	4/4	1	NM_000621.5	ENSP00000437737	P1
HTR2A	ENST00000543956.5	c.866A>C	p.His289Pro	missense_variant	3/3	1		ENSP00000441861

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000609 AC: 89 AN: 1461762 Hom.: 0 Cov.: 32 AF XY: 0.0000605 AC XY: 44 AN XY: 727182

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000764

Gnomad4 OTH exome AF: 0.0000662

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000658 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 05, 2024

The c.1355A>C (p.H452P) alteration is located in exon 4 (coding exon 3) of the HTR2A gene. This alteration results from a A to C substitution at nucleotide position 1355, causing the histidine (H) at amino acid position 452 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	0.23
DANN	Benign	0.19
DEOGEN2	Benign	0.14	T;T;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.46	.;T;T
M_CAP	Benign	0.0089	T
MetaRNN	Benign	0.049	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.20	N;N;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.52	N;N;N
REVEL	Benign	0.046
Sift	Benign	0.25	T;T;T
Sift4G	Benign	0.36	T;T;T
Polyphen		0.0	B;B;.
Vest4		0.050
MutPred		0.11		Gain of glycosylation at H452 (P = 0.0565);Gain of glycosylation at H452 (P = 0.0565);.;
MVP		0.36
MPC		0.41
ClinPred		0.037	T
GERP RS		-1.5
Varity_R		0.073
gMVP		0.30

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs768425509; hg19: chr13-47409033;