Genetic Variant HCRTR2:p.Ile308Phe (chr6-55277539-A-T) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_001384272.1(HCRTR2):c.922A>T(p.Ile308Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I308V) has been classified as Benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

HCRTR2
NM_001384272.1 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.56

Publications

74 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.2885179).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
HCRTR2	NM_001384272.1 link	c.922A>T	p.Ile308Phe	missense_variant	Exon 5 of 7	ENST00000370862.4	NP_001371201.1
HCRTR2	NM_001526.5 link	c.922A>T	p.Ile308Phe	missense_variant	Exon 6 of 8		NP_001517.2
HCRTR2	XM_017010798.2 link	c.922A>T	p.Ile308Phe	missense_variant	Exon 6 of 9		XP_016866287.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HCRTR2	ENST00000370862.4 link	c.922A>T	p.Ile308Phe	missense_variant	Exon 5 of 7	1	NM_001384272.1	ENSP00000359899.3		O43614
HCRTR2	ENST00000615358.4 link	c.922A>T	p.Ile308Phe	missense_variant	Exon 6 of 8	1		ENSP00000477548.1		O43614

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

250970

AF XY:

0.00000737

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000137

AC:

AN:

1461730

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727162

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33476

American (AMR)

AF:

0.00

AC:

AN:

44692

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39668

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111930

Other (OTH)

AF:

0.00

AC:

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.36

CADD

Uncertain

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.39

T;T

Eigen

Benign

0.13

Eigen_PC

Uncertain

0.28

FATHMM_MKL

Uncertain

0.87

LIST_S2

Uncertain

0.88

D;.

M_CAP

Benign

0.034

MetaRNN

Benign

0.29

T;T

MetaSVM

Benign

-0.92

MutationAssessor

Benign

1.5

L;L

PhyloP100

7.6

PrimateAI

Uncertain

0.72

PROVEAN

Benign

-2.3

.;N

REVEL

Benign

0.27

Sift

Uncertain

0.0060

.;D

Sift4G

Uncertain

0.019

D;D

Polyphen

0.029

B;B

Vest4

0.33

MutPred

0.62

Loss of MoRF binding (P = 0.1145);Loss of MoRF binding (P = 0.1145);

MVP

0.78

MPC

0.69

ClinPred

0.77

GERP RS

6.1

Varity_R

0.44

gMVP

0.82

Mutation Taster

=67/33

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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