Genetic Variant NM_000621.5:c.614-20489G>C (chr13-46856128-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.614-20489G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.158 in 152,168 control chromosomes in the GnomAD database, including 2,384 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 0.16 ( 2384 hom., cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

HTR2A
NM_000621.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.823

Publications

2 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=-0.91).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.273 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HTR2A	NM_000621.5 link	c.614-20489G>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.614-20489G>C	intron_variant	Intron 3 of 3	1	NM_000621.5	ENSP00000437737.1	P28223-1
HTR2A	ENST00000543956.5 link	c.125-20489G>C	intron_variant	Intron 2 of 2	1		ENSP00000441861.2	A0A7P0PKG8
HTR2A-AS1	ENST00000430913.3 link	n.351C>G	non_coding_transcript_exon_variant	Exon 4 of 4	3
HTR2A-AS1	ENST00000455126.5 link	n.123C>G	non_coding_transcript_exon_variant	Exon 2 of 2	5

Frequencies

GnomAD3 genomes

AF:

0.158

AC:

24068

AN:

152050

Hom.:

2373

Cov.:

show subpopulations

Gnomad AFR

AF:

0.277

Gnomad AMI

AF:

0.0559

Gnomad AMR

AF:

0.148

Gnomad ASJ

AF:

0.181

Gnomad EAS

AF:

0.192

Gnomad SAS

AF:

0.154

Gnomad FIN

AF:

0.0575

Gnomad MID

AF:

0.206

Gnomad NFE

AF:

0.102

Gnomad OTH

AF:

0.154

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

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:

0.00

AC:

AN:

Other (OTH)

AC:

AN:

GnomAD4 genome

AF:

0.158

AC:

24117

AN:

152168

Hom.:

2384

Cov.:

AF XY:

0.157

AC XY:

11703

AN XY:

74404

show subpopulations

African (AFR)

AF:

0.277

AC:

11495

AN:

41480

American (AMR)

AF:

0.148

AC:

2260

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.181

AC:

626

AN:

3468

East Asian (EAS)

AF:

0.192

AC:

992

AN:

5174

South Asian (SAS)

AF:

0.154

AC:

743

AN:

4816

European-Finnish (FIN)

AF:

0.0575

AC:

610

AN:

10604

Middle Eastern (MID)

AF:

0.211

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.102

AC:

6948

AN:

68018

Other (OTH)

AF:

0.156

AC:

330

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

986

1972

2958

3944

4930

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

254

508

762

1016

1270

<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:

0.0358

Hom.:

Bravo

AF:

0.171

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.91

CADD

Benign

0.42

(source)

DANN

Benign

0.46

PhyloP100

-0.82

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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