13-46834993-C-G

Variant names:

• chr13-46834993-C-G
• rs1593423658
• NM_000621.5:c.1260G>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_000621.5(HTR2A):​c.1260G>C​(p.Lys420Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. K420K) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: HTR2A NM_000621.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.701
• Publications: 0 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.04620552).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000621.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HTR2A	NM_000621.5	MANE Select	c.1260G>C	p.Lys420Asn	missense	Exon 4 of 4	NP_000612.1	P28223-1
	HTR2A	NM_001378924.1		c.1260G>C	p.Lys420Asn	missense	Exon 4 of 4	NP_001365853.1	P28223-1
	HTR2A	NM_001165947.5		c.771G>C	p.Lys257Asn	missense	Exon 3 of 3	NP_001159419.2	A0A7P0PKG8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HTR2A	ENST00000542664.4	TSL:1 MANE Select	c.1260G>C	p.Lys420Asn	missense	Exon 4 of 4	ENSP00000437737.1	P28223-1
	HTR2A	ENST00000543956.5	TSL:1	c.771G>C	p.Lys257Asn	missense	Exon 3 of 3	ENSP00000441861.2	A0A7P0PKG8
	HTR2A	ENST00000941626.1		c.1260G>C	p.Lys420Asn	missense	Exon 3 of 3	ENSP00000611685.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	14
DANN	Benign	0.77
DEOGEN2	Benign	0.073	T
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.35
FATHMM_MKL	Benign	0.64	D
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.0023	T
MetaRNN	Benign	0.046	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.55	N
PhyloP100		0.70
PrimateAI	Benign	0.40	T
PROVEAN	Benign	0.21	N
REVEL	Benign	0.19
Sift	Benign	0.73	T
Sift4G	Benign	0.48	T
Polyphen		0.0	B
Vest4		0.045
MutPred		0.40		Loss of methylation at K420 (P = 0.0126)
MVP		0.45
MPC		0.31
ClinPred		0.17	T
GERP RS		1.8
Varity_R		0.053
gMVP		0.26
Mutation Taster		=69/31	polymorphism

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: rs1593423658; hg19: chr13-47409128;