Genetic Variant HTR2A:c.614-20502G>C (chr13-46856141-C-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_000621.5(HTR2A):c.614-20502G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.317 in 152,104 control chromosomes in the GnomAD database, including 7,756 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.32 ( 7756 hom., cov: 32)

Exomes 𝑓: 0.17 ( 0 hom. )

Consequence

HTR2A
NM_000621.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.315

Publications

6 publications found

Variant links:

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]

HTR2A links:

HTR2A-AS1 (HGNC:40289): (HTR2A antisense RNA 1)

HTR2A-AS1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.95).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.349 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HTR2A	NM_000621.5 link	c.614-20502G>C		intron_variant	Intron 3 of 3	ENST00000542664.4	NP_000612.1	P28223-1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
HTR2A	ENST00000542664.4 link	c.614-20502G>C	intron_variant	Intron 3 of 3	1	NM_000621.5	ENSP00000437737.1	P28223-1
HTR2A	ENST00000543956.5 link	c.125-20502G>C	intron_variant	Intron 2 of 2	1		ENSP00000441861.2	A0A7P0PKG8
HTR2A-AS1	ENST00000430913.3 link	n.364C>G	non_coding_transcript_exon_variant	Exon 4 of 4	3
HTR2A-AS1	ENST00000455126.5 link	n.136C>G	non_coding_transcript_exon_variant	Exon 2 of 2	5

Frequencies

GnomAD3 genomes

AF:

0.317

AC:

48242

AN:

151980

Hom.:

7747

Cov.:

show subpopulations

Gnomad AFR

AF:

0.280

Gnomad AMI

AF:

0.362

Gnomad AMR

AF:

0.257

Gnomad ASJ

AF:

0.367

Gnomad EAS

AF:

0.246

Gnomad SAS

AF:

0.333

Gnomad FIN

AF:

0.336

Gnomad MID

AF:

0.263

Gnomad NFE

AF:

0.353

Gnomad OTH

AF:

0.319

GnomAD4 exome

AF:

0.167

AC:

AN:

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.167

AC:

AN:

Other (OTH)

AC:

AN:

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.317

AC:

48253

AN:

152098

Hom.:

7756

Cov.:

AF XY:

0.315

AC XY:

23398

AN XY:

74364

show subpopulations

African (AFR)

AF:

0.280

AC:

11595

AN:

41468

American (AMR)

AF:

0.256

AC:

3919

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.367

AC:

1273

AN:

3468

East Asian (EAS)

AF:

0.246

AC:

1274

AN:

5180

South Asian (SAS)

AF:

0.332

AC:

1597

AN:

4816

European-Finnish (FIN)

AF:

0.336

AC:

3552

AN:

10572

Middle Eastern (MID)

AF:

0.252

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.352

AC:

23965

AN:

67988

Other (OTH)

AF:

0.320

AC:

675

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1711

3423

5134

6846

8557

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

500

1000

1500

2000

2500

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.198

Hom.:

431

Bravo

AF:

0.312

Asia WGS

AF:

0.302

AC:

1050

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.95

CADD

Benign

1.4

(source)

DANN

Benign

0.49

PhyloP100

0.32

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.10

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over