13-46895833-G-T

Position:

• chr13-46895833-G-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_000621.5(HTR2A):​c.74C>A​(p.Thr25Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0216 in 1,614,066 control chromosomes in the GnomAD database, including 410 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.016 (27 hom., cov: 32)
  • Exomes 𝑓: 0.022 (383 hom.)
• Consequence: HTR2A NM_000621.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.85

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0022446513).
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0164 (2505/152298) while in subpopulation SAS AF= 0.0263 (127/4824). AF 95% confidence interval is 0.0226. There are 27 homozygotes in gnomad4. There are 1248 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 2505 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HTR2A	NM_000621.5	c.74C>A	p.Thr25Asn	missense_variant	2/4	ENST00000542664.4	NP_000612.1
HTR2A	NM_001378924.1	c.74C>A	p.Thr25Asn	missense_variant	2/4		NP_001365853.1
HTR2A	NM_001165947.5	c.-78+841C>A		intron_variant			NP_001159419.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HTR2A	ENST00000542664.4	c.74C>A	p.Thr25Asn	missense_variant	2/4	1	NM_000621.5	ENSP00000437737	P1
HTR2A	ENST00000543956.5	c.-78+841C>A		intron_variant		1		ENSP00000441861
HTR2A	ENST00000612998.1			upstream_gene_variant				ENSP00000482708

Frequencies

GnomAD3 genomes AF: 0.0165 AC: 2506 AN: 152180 Hom.: 27 Cov.: 32

Gnomad AFR AF: 0.00352

Gnomad AMI AF: 0.0329

Gnomad AMR AF: 0.0126

Gnomad ASJ AF: 0.0271

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0263

Gnomad FIN AF: 0.0274

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0234

Gnomad OTH AF: 0.0134

GnomAD3 exomes AF: 0.0184 AC: 4621 AN: 251412 Hom.: 60 AF XY: 0.0197 AC XY: 2681 AN XY: 135886

Gnomad AFR exome AF: 0.00351

Gnomad AMR exome AF: 0.00917

Gnomad ASJ exome AF: 0.0278

Gnomad EAS exome AF: 0.000272

Gnomad SAS exome AF: 0.0221

Gnomad FIN exome AF: 0.0245

Gnomad NFE exome AF: 0.0232

Gnomad OTH exome AF: 0.0199

GnomAD4 exome AF: 0.0222 AC: 32386 AN: 1461768 Hom.: 383 Cov.: 33 AF XY: 0.0223 AC XY: 16200 AN XY: 727192

Gnomad4 AFR exome AF: 0.00305

Gnomad4 AMR exome AF: 0.00950

Gnomad4 ASJ exome AF: 0.0266

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.0221

Gnomad4 FIN exome AF: 0.0236

Gnomad4 NFE exome AF: 0.0240

Gnomad4 OTH exome AF: 0.0204

GnomAD4 genome AF: 0.0164 AC: 2505 AN: 152298 Hom.: 27 Cov.: 32 AF XY: 0.0168 AC XY: 1248 AN XY: 74466

Gnomad4 AFR AF: 0.00351

Gnomad4 AMR AF: 0.0126

Gnomad4 ASJ AF: 0.0271

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0263

Gnomad4 FIN AF: 0.0274

Gnomad4 NFE AF: 0.0234

Gnomad4 OTH AF: 0.0132

Alfa AF: 0.0213 Hom.: 56

Bravo AF: 0.0146

TwinsUK AF: 0.0227 AC: 84

ALSPAC AF: 0.0228 AC: 88

ESP6500AA AF: 0.00545 AC: 24

ESP6500EA AF: 0.0242 AC: 208

ExAC AF: 0.0185 AC: 2250

Asia WGS AF: 0.00866 AC: 30 AN: 3478

EpiCase AF: 0.0217

EpiControl AF: 0.0236

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	15
DANN	Benign	0.97
DEOGEN2	Benign	0.083	T;T
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.32
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.74	.;T
MetaRNN	Benign	0.0022	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N;N
MutationTaster	Benign	1.0	D;N;N
PrimateAI	Benign	0.24	T
PROVEAN	Benign	0.020	N;N
REVEL	Benign	0.12
Sift	Benign	0.16	T;T
Sift4G	Benign	0.35	T;T
Polyphen		0.019	B;B
Vest4		0.057
MPC		0.36
ClinPred		0.028	T
GERP RS		3.4
Varity_R		0.058
gMVP		0.55

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

LitVar

Other links and lift over

dbSNP: rs1805055; hg19: chr13-47469968; COSMIC: COSV66327897; COSMIC: COSV66327897;