13-46835596-C-T

Variant names:

• chr13-46835596-C-T
• rs35480504
• NM_000621.5:c.657G>A

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_Moderate BP6_Very_Strong BP7 BS2

The NM_000621.5(HTR2A):​c.657G>A​(p.Ser219Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00126 in 1,613,904 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00093 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (0 hom.)
• Consequence: HTR2A NM_000621.5 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.00
• 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: Benign. The variant received -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.33).
• BP6: Variant 13-46835596-C-T is Benign according to our data. Variant chr13-46835596-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 712185.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2 with no splicing effect.
• BS2: High AC in GnomAd4 at 142 AD gene.

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.657G>A	p.Ser219Ser	synonymous	Exon 4 of 4	NP_000612.1	P28223-1
	HTR2A	NM_001378924.1		c.657G>A	p.Ser219Ser	synonymous	Exon 4 of 4	NP_001365853.1	P28223-1
	HTR2A	NM_001165947.5		c.168G>A	p.Ser56Ser	synonymous	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.657G>A	p.Ser219Ser	synonymous	Exon 4 of 4	ENSP00000437737.1	P28223-1
	HTR2A	ENST00000543956.5	TSL:1	c.168G>A	p.Ser56Ser	synonymous	Exon 3 of 3	ENSP00000441861.2	A0A7P0PKG8
	HTR2A	ENST00000941626.1		c.657G>A	p.Ser219Ser	synonymous	Exon 3 of 3	ENSP00000611685.1

Frequencies

GnomAD3 genomes AF: 0.000933 AC: 142 AN: 152124 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000434

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00293

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00129

Gnomad OTH AF: 0.000955

GnomAD2 exomes AF: 0.00106 AC: 265 AN: 250820 AF XY: 0.000996

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.0000869

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00259

Gnomad NFE exome AF: 0.00166

Gnomad OTH exome AF: 0.00131

GnomAD4 exome AF: 0.00129 AC: 1889 AN: 1461662 Hom.: 0 Cov.: 33 AF XY: 0.00125 AC XY: 906 AN XY: 727128

African (AFR) AF: 0.000209 AC: 7 AN: 33464

American (AMR) AF: 0.000134 AC: 6 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39694

South Asian (SAS) AF: 0.000174 AC: 15 AN: 86246

European-Finnish (FIN) AF: 0.00268 AC: 143 AN: 53406

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5762

European-Non Finnish (NFE) AF: 0.00148 AC: 1651 AN: 1111884

Other (OTH) AF: 0.00103 AC: 62 AN: 60390

GnomAD4 genome AF: 0.000933 AC: 142 AN: 152242 Hom.: 1 Cov.: 32 AF XY: 0.000846 AC XY: 63 AN XY: 74426

African (AFR) AF: 0.000433 AC: 18 AN: 41564

American (AMR) AF: 0.000131 AC: 2 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4816

European-Finnish (FIN) AF: 0.00293 AC: 31 AN: 10586

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00129 AC: 88 AN: 67996

Other (OTH) AF: 0.000945 AC: 2 AN: 2116

Alfa AF: 0.00110 Hom.: 0

Bravo AF: 0.000706

EpiCase AF: 0.00120

EpiControl AF: 0.000593

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.33
CADD	Benign	6.3
DANN	Benign	0.66
PhyloP100		2.0
Mutation Taster		=88/12	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: rs35480504; hg19: chr13-47409731; COSMIC: COSV101096822;