13-46835117-A-G

Position:

• chr13-46835117-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_000621.5(HTR2A):​c.1136T>C​(p.Val379Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: HTR2A NM_000621.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.32

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.935

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HTR2A	NM_000621.5	c.1136T>C	p.Val379Ala	missense_variant	4/4	ENST00000542664.4	NP_000612.1
HTR2A	NM_001378924.1	c.1136T>C	p.Val379Ala	missense_variant	4/4		NP_001365853.1
HTR2A	NM_001165947.5	c.647T>C	p.Val216Ala	missense_variant	3/3		NP_001159419.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HTR2A	ENST00000542664.4	c.1136T>C	p.Val379Ala	missense_variant	4/4	1	NM_000621.5	ENSP00000437737	P1
HTR2A	ENST00000543956.5	c.647T>C	p.Val216Ala	missense_variant	3/3	1		ENSP00000441861

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

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

Mar 21, 2024

The c.1136T>C (p.V379A) alteration is located in exon 4 (coding exon 3) of the HTR2A gene. This alteration results from a T to C substitution at nucleotide position 1136, causing the valine (V) at amino acid position 379 to be replaced by an alanine (A). 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	Pathogenic	0.90
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.60	D;D;.
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	.;D;D
M_CAP	Benign	0.067	D
MetaRNN	Pathogenic	0.93	D;D;D
MetaSVM	Uncertain	-0.11	T
MutationAssessor	Pathogenic	3.0	M;M;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-3.2	D;D;D
REVEL	Uncertain	0.61
Sift	Uncertain	0.0010	D;D;D
Sift4G	Uncertain	0.0020	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.75
MutPred		0.83		Loss of stability (P = 0.0456);Loss of stability (P = 0.0456);.;
MVP		0.71
MPC		1.0
ClinPred		0.99	D
GERP RS		5.6
Varity_R		0.76
gMVP		0.72

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr13-47409252;