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.

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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
HTR2A	NM_000621.5	MANE Select	c.614-20502G>C	intron	N/A	NP_000612.1
HTR2A-AS1	NR_046612.1		n.283C>G	non_coding_transcript_exon	Exon 3 of 3
HTR2A-AS1	NR_103752.1		n.139C>G	non_coding_transcript_exon	Exon 2 of 2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
HTR2A	ENST00000542664.4	TSL:1 MANE Select	c.614-20502G>C	intron	N/A	ENSP00000437737.1
HTR2A	ENST00000543956.5	TSL:1	c.125-20502G>C	intron	N/A	ENSP00000441861.2
HTR2A-AS1	ENST00000430913.3	TSL:3	n.364C>G	non_coding_transcript_exon	Exon 4 of 4

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 v4.9

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over