dbSNP rs41271310: HCRTR2:p.Pro10Ser (chr6-55174615-C-T) – ACMG Classification: Benign (-9 pts)

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_001384272.1(HCRTR2):c.28C>T(p.Pro10Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00296 in 1,614,038 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars). Synonymous variant affecting the same amino acid position (i.e. P10P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0019 ( 1 hom., cov: 30)

Exomes 𝑓: 0.0031 ( 12 hom. )

Consequence

HCRTR2
NM_001384272.1 missense

Scores

Clinical Significance

Likely benign no assertion criteria provided B:1

Conservation

PhyloP100: 4.26

Publications

10 publications found

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 was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0052185953).

BP6

Variant 6-55174615-C-T is Benign according to our data. Variant chr6-55174615-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 3042775.Status of the report is no_assertion_criteria_provided, 0 stars.

BS2

High Homozygotes in GnomAdExome4 at 12 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
HCRTR2	NM_001384272.1 link	c.28C>T	p.Pro10Ser	missense_variant	Exon 1 of 7	ENST00000370862.4	NP_001371201.1
HCRTR2	NM_001526.5 link	c.28C>T	p.Pro10Ser	missense_variant	Exon 2 of 8		NP_001517.2
HCRTR2	XM_017010798.2 link	c.28C>T	p.Pro10Ser	missense_variant	Exon 2 of 9		XP_016866287.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HCRTR2	ENST00000370862.4 link	c.28C>T	p.Pro10Ser	missense_variant	Exon 1 of 7	1	NM_001384272.1	ENSP00000359899.3		O43614
HCRTR2	ENST00000615358.4 link	c.28C>T	p.Pro10Ser	missense_variant	Exon 2 of 8	1		ENSP00000477548.1		O43614

Frequencies

GnomAD3 genomes

AF:

0.00193

AC:

294

AN:

152060

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000435

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.00164

Gnomad ASJ

AF:

0.00230

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00415

Gnomad FIN

AF:

0.000377

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00316

Gnomad OTH

AF:

0.00143

GnomAD2 exomes

AF:

0.00250

AC:

628

AN:

251364

AF XY:

0.00278

show subpopulations

Gnomad AFR exome

AF:

0.000431

Gnomad AMR exome

AF:

0.00116

Gnomad ASJ exome

AF:

0.00109

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000647

Gnomad NFE exome

AF:

0.00339

Gnomad OTH exome

AF:

0.00212

GnomAD4 exome

AF:

0.00306

AC:

4478

AN:

1461860

Hom.:

Cov.:

AF XY:

0.00311

AC XY:

2260

AN XY:

727238

show subpopulations

African (AFR)

AF:

0.000448

AC:

AN:

33478

American (AMR)

AF:

0.00116

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00180

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.00561

AC:

484

AN:

86258

European-Finnish (FIN)

AF:

0.000505

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00208

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00331

AC:

3682

AN:

1111988

Other (OTH)

AF:

0.00263

AC:

159

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

243

486

730

973

1216

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

150

300

450

600

750

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00193

AC:

294

AN:

152178

Hom.:

Cov.:

AF XY:

0.00196

AC XY:

146

AN XY:

74388

show subpopulations

African (AFR)

AF:

0.000433

AC:

AN:

41528

American (AMR)

AF:

0.00164

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00230

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5154

South Asian (SAS)

AF:

0.00416

AC:

AN:

4812

European-Finnish (FIN)

AF:

0.000377

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00316

AC:

215

AN:

68000

Other (OTH)

AF:

0.00142

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00271

Hom.:

Bravo

AF:

0.00187

TwinsUK

AF:

0.00405

AC:

ALSPAC

AF:

0.00285

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00314

AC:

ExAC

AF:

0.00261

AC:

317

Asia WGS

AF:

0.00231

AC:

AN:

3478

EpiCase

AF:

0.00289

EpiControl

AF:

0.00308

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

HCRTR2-related disorder

Benign:1

Aug 09, 2022

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely 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

0.063

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.13

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.055

T;T

Eigen

Benign

-0.40

Eigen_PC

Benign

-0.26

FATHMM_MKL

Uncertain

0.83

LIST_S2

Benign

0.77

T;.

M_CAP

Benign

0.018

MetaRNN

Benign

0.0052

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.4

L;L

PhyloP100

4.3

PrimateAI

Benign

0.30

PROVEAN

Benign

0.0

.;N

REVEL

Benign

0.27

Sift

Benign

0.087

.;T

Sift4G

Benign

0.087

T;T

Polyphen

0.0010

B;B

Vest4

0.74

MVP

0.72

MPC

0.39

ClinPred

0.027

GERP RS

4.1

PromoterAI

0.10

Neutral

(source)

Varity_R

0.098

gMVP

0.50

Mutation Taster

=81/19

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over