Genetic Variant NM_001384272.1:c.31C>A (chr6-55174618-C-A) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_001384272.1(HCRTR2):c.31C>A(p.Pro11Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00718 in 1,614,056 control chromosomes in the GnomAD database, including 49 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0059 ( 3 hom., cov: 31)

Exomes 𝑓: 0.0073 ( 46 hom. )

Consequence

HCRTR2
NM_001384272.1 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.807

Publications

13 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 -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0064996183).

BS2

High Homozygotes in GnomAd4 at 3 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001384272.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HCRTR2	NM_001384272.1	MANE Select	c.31C>A	p.Pro11Thr	missense	Exon 1 of 7	NP_001371201.1
	HCRTR2	NM_001526.5		c.31C>A	p.Pro11Thr	missense	Exon 2 of 8	NP_001517.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HCRTR2	ENST00000370862.4	TSL:1 MANE Select	c.31C>A	p.Pro11Thr	missense	Exon 1 of 7	ENSP00000359899.3
	HCRTR2	ENST00000615358.4	TSL:1	c.31C>A	p.Pro11Thr	missense	Exon 2 of 8	ENSP00000477548.1

Frequencies

GnomAD3 genomes

AF:

0.00593

AC:

902

AN:

152084

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00152

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.0107

Gnomad ASJ

AF:

0.00375

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00104

Gnomad FIN

AF:

0.00179

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00919

Gnomad OTH

AF:

0.00623

GnomAD2 exomes

AF:

0.00486

AC:

1223

AN:

251400

AF XY:

0.00468

show subpopulations

Gnomad AFR exome

AF:

0.00123

Gnomad AMR exome

AF:

0.00520

Gnomad ASJ exome

AF:

0.00318

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00148

Gnomad NFE exome

AF:

0.00789

Gnomad OTH exome

AF:

0.00684

GnomAD4 exome

AF:

0.00731

AC:

10684

AN:

1461854

Hom.:

Cov.:

AF XY:

0.00698

AC XY:

5077

AN XY:

727228

show subpopulations

African (AFR)

AF:

0.00185

AC:

AN:

33480

American (AMR)

AF:

0.00514

AC:

230

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00341

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39696

South Asian (SAS)

AF:

0.000614

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00182

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00156

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00874

AC:

9722

AN:

1111980

Other (OTH)

AF:

0.00695

AC:

420

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

581

1162

1744

2325

2906

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

364

728

1092

1456

1820

<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:

0.00593

AC:

902

AN:

152202

Hom.:

Cov.:

AF XY:

0.00555

AC XY:

413

AN XY:

74418

show subpopulations

African (AFR)

AF:

0.00152

AC:

AN:

41552

American (AMR)

AF:

0.0107

AC:

163

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.00375

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5156

South Asian (SAS)

AF:

0.00104

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00179

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00919

AC:

625

AN:

67990

Other (OTH)

AF:

0.00616

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

142

190

237

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00694

Hom.:

Bravo

AF:

0.00580

TwinsUK

AF:

0.00944

AC:

ALSPAC

AF:

0.00960

AC:

ESP6500AA

AF:

0.00204

AC:

ESP6500EA

AF:

0.00756

AC:

ExAC

AF:

0.00463

AC:

562

EpiCase

AF:

0.00747

EpiControl

AF:

0.00688

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.066

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.11

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.16

Eigen

Benign

-0.60

Eigen_PC

Benign

-0.49

FATHMM_MKL

Benign

0.73

LIST_S2

Benign

0.80

MetaRNN

Benign

0.0065

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.5

PhyloP100

0.81

PrimateAI

Benign

0.34

PROVEAN

Benign

-0.19

REVEL

Benign

0.26

Sift

Benign

0.072

Sift4G

Benign

0.39

Polyphen

0.035

Vest4

0.76

MVP

0.66

MPC

0.44

ClinPred

0.0058

GERP RS

3.1

PromoterAI

-0.075

Neutral

(source)

Varity_R

0.052

gMVP

0.30

Mutation Taster

=88/12

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over