Variant 6-55277539-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBA1

The NM_001384272.1(HCRTR2):c.922A>G(p.Ile308Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.813 in 1,613,552 control chromosomes in the GnomAD database, including 534,525 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: 𝑓 0.84 ( 54364 hom., cov: 33)

Exomes 𝑓: 0.81 ( 480161 hom. )

Consequence

HCRTR2
NM_001384272.1 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 7.56

Variant links:

Genes affected

HCRTR2 (HGNC:4849): (hypocretin receptor 2) The protein encoded by this gene is a G-protein coupled receptor involved in the regulation of feeding behavior. The encoded protein binds the hypothalamic neuropeptides orexin A and orexin B. A related gene (HCRTR1) encodes a G-protein coupled receptor that selectively binds orexin A. [provided by RefSeq, Jan 2009]

HCRTR2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=6.7995734E-7).

BP6

Variant 6-55277539-A-G is Benign according to our data. Variant chr6-55277539-A-G is described in ClinVar as [Benign]. Clinvar id is 3059587.Status of the report is criteria_provided_single_submitter, 1 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.912 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
HCRTR2	NM_001384272.1 linkuse as main transcript	c.922A>G	p.Ile308Val	missense_variant	5/7	ENST00000370862.4
HCRTR2	NM_001526.5 linkuse as main transcript	c.922A>G	p.Ile308Val	missense_variant	6/8
HCRTR2	XM_017010798.2 linkuse as main transcript	c.922A>G	p.Ile308Val	missense_variant	6/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HCRTR2	ENST00000370862.4 linkuse as main transcript	c.922A>G	p.Ile308Val	missense_variant	5/7	1	NM_001384272.1	P1
HCRTR2	ENST00000615358.4 linkuse as main transcript	c.922A>G	p.Ile308Val	missense_variant	6/8	1		P1

Frequencies

GnomAD3 genomes

AF:

0.843

AC:

128305

AN:

152156

Hom.:

54314

Cov.:

show subpopulations

Gnomad AFR

AF:

0.890

Gnomad AMI

AF:

0.930

Gnomad AMR

AF:

0.876

Gnomad ASJ

AF:

0.888

Gnomad EAS

AF:

0.934

Gnomad SAS

AF:

0.871

Gnomad FIN

AF:

0.818

Gnomad MID

AF:

0.921

Gnomad NFE

AF:

0.798

Gnomad OTH

AF:

0.860

GnomAD3 exomes

AF:

0.843

AC:

211479

AN:

250970

Hom.:

89506

AF XY:

0.841

AC XY:

114041

AN XY:

135626

show subpopulations

Gnomad AFR exome

AF:

0.893

Gnomad AMR exome

AF:

0.894

Gnomad ASJ exome

AF:

0.893

Gnomad EAS exome

AF:

0.944

Gnomad SAS exome

AF:

0.864

Gnomad FIN exome

AF:

0.813

Gnomad NFE exome

AF:

0.799

Gnomad OTH exome

AF:

0.838

GnomAD4 exome

AF:

0.809

AC:

1182709

AN:

1461278

Hom.:

480161

Cov.:

AF XY:

0.812

AC XY:

590104

AN XY:

726970

show subpopulations

Gnomad4 AFR exome

AF:

0.896

Gnomad4 AMR exome

AF:

0.892

Gnomad4 ASJ exome

AF:

0.893

Gnomad4 EAS exome

AF:

0.947

Gnomad4 SAS exome

AF:

0.866

Gnomad4 FIN exome

AF:

0.812

Gnomad4 NFE exome

AF:

0.790

Gnomad4 OTH exome

AF:

0.829

GnomAD4 genome

AF:

0.843

AC:

128415

AN:

152274

Hom.:

54364

Cov.:

AF XY:

0.848

AC XY:

63110

AN XY:

74442

show subpopulations

Gnomad4 AFR

AF:

0.890

Gnomad4 AMR

AF:

0.876

Gnomad4 ASJ

AF:

0.888

Gnomad4 EAS

AF:

0.934

Gnomad4 SAS

AF:

0.872

Gnomad4 FIN

AF:

0.818

Gnomad4 NFE

AF:

0.798

Gnomad4 OTH

AF:

0.857

Alfa

AF:

0.813

Hom.:

122763

Bravo

AF:

0.849

TwinsUK

AF:

0.797

AC:

2955

ALSPAC

AF:

0.789

AC:

3040

ESP6500AA

AF:

0.884

AC:

3897

ESP6500EA

AF:

0.794

AC:

6825

ExAC

AF:

0.839

AC:

101840

Asia WGS

AF:

0.890

AC:

3095

AN:

3478

EpiCase

AF:

0.811

EpiControl

AF:

0.806

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

HCRTR2-related disorder

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 16, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.043

BayesDel_addAF

Benign

-0.71

BayesDel_noAF

Benign

-0.64

CADD

Benign

DANN

Benign

0.77

DEOGEN2

Benign

0.044

T;T

Eigen

Benign

-0.45

Eigen_PC

Benign

-0.14

FATHMM_MKL

Benign

0.15

LIST_S2

Benign

0.20

T;.

MetaRNN

Benign

6.8e-7

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.98

N;N

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.72

Sift4G

Benign

1.0

T;T

Polyphen

0.0

B;B

Vest4

0.062

MPC

0.32

ClinPred

0.0091

GERP RS

6.1

Varity_R

0.091

gMVP

0.33

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over