Variant 6-55277392-T-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.775T>A(p.Ser259Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000273 in 1,613,302 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 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 0.000033 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000027 ( 0 hom. )

Consequence

HCRTR2
NM_001384272.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.89

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 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=0.07874784).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
HCRTR2	NM_001384272.1 linkuse as main transcript	c.775T>A	p.Ser259Thr	missense_variant	5/7	ENST00000370862.4	NP_001371201.1
HCRTR2	NM_001526.5 linkuse as main transcript	c.775T>A	p.Ser259Thr	missense_variant	6/8		NP_001517.2
HCRTR2	XM_017010798.2 linkuse as main transcript	c.775T>A	p.Ser259Thr	missense_variant	6/9		XP_016866287.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HCRTR2	ENST00000370862.4 linkuse as main transcript	c.775T>A	p.Ser259Thr	missense_variant	5/7	1	NM_001384272.1	ENSP00000359899.3		O43614
HCRTR2	ENST00000615358.4 linkuse as main transcript	c.775T>A	p.Ser259Thr	missense_variant	6/8	1		ENSP00000477548.1		O43614

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000199

AC:

AN:

251078

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135714

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000440

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000267

AC:

AN:

1461100

Hom.:

Cov.:

AF XY:

0.0000193

AC XY:

AN XY:

726934

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:

0.0000324

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000329

AC:

AN:

152202

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74350

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000710

Hom.:

Bravo

AF:

0.0000340

ExAC

AF:

0.00000824

AC:

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

Oct 21, 2024

The c.775T>A (p.S259T) alteration is located in exon 5 (coding exon 5) of the HCRTR2 gene. This alteration results from a T to A substitution at nucleotide position 775, causing the serine (S) at amino acid position 259 to be replaced by a threonine (T). 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

0.082

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.48

CADD

Benign

DANN

Benign

0.16

DEOGEN2

Benign

0.038

T;T

Eigen

Benign

-0.39

Eigen_PC

Benign

-0.22

FATHMM_MKL

Uncertain

0.77

LIST_S2

Benign

0.79

T;.

M_CAP

Benign

0.0078

MetaRNN

Benign

0.079

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.010

N;N

PrimateAI

Uncertain

0.61

PROVEAN

Benign

0.24

.;N

REVEL

Benign

0.065

Sift

Benign

0.79

.;T

Sift4G

Benign

1.0

T;T

Polyphen

0.0030

B;B

Vest4

0.15

MVP

0.71

MPC

0.36

ClinPred

0.11

GERP RS

4.9

Varity_R

0.18

gMVP

0.36

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