Variant 6-55277444-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001384272.1(HCRTR2):c.827G>A(p.Arg276Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000479 in 1,461,762 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

HCRTR2
NM_001384272.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.87

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 made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.14074218).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
HCRTR2	NM_001384272.1 linkuse as main transcript	c.827G>A	p.Arg276Gln	missense_variant	5/7	ENST00000370862.4
HCRTR2	NM_001526.5 linkuse as main transcript	c.827G>A	p.Arg276Gln	missense_variant	6/8
HCRTR2	XM_017010798.2 linkuse as main transcript	c.827G>A	p.Arg276Gln	missense_variant	6/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HCRTR2	ENST00000370862.4 linkuse as main transcript	c.827G>A	p.Arg276Gln	missense_variant	5/7	1	NM_001384272.1	P1
HCRTR2	ENST00000615358.4 linkuse as main transcript	c.827G>A	p.Arg276Gln	missense_variant	6/8	1		P1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000479

AC:

AN:

1461762

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727176

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000630

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 02, 2022

The c.827G>A (p.R276Q) alteration is located in exon 5 (coding exon 5) of the HCRTR2 gene. This alteration results from a G to A substitution at nucleotide position 827, causing the arginine (R) at amino acid position 276 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.071

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.39

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.057

T;T

Eigen

Benign

-0.28

Eigen_PC

Benign

-0.075

FATHMM_MKL

Uncertain

0.79

LIST_S2

Benign

0.78

T;.

M_CAP

Benign

0.0081

MetaRNN

Benign

0.14

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.69

N;N

MutationTaster

Benign

0.59

PrimateAI

Benign

0.44

PROVEAN

Benign

0.32

.;N

REVEL

Benign

0.060

Sift

Benign

0.65

.;T

Sift4G

Benign

0.69

T;T

Polyphen

0.027

B;B

Vest4

0.19

MutPred

0.37

Loss of MoRF binding (P = 0.0286);Loss of MoRF binding (P = 0.0286);

MVP

0.82

MPC

0.45

ClinPred

0.62

GERP RS

5.2

Varity_R

0.073

gMVP

0.39

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

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