6-55277444-G-A

Position:

• chr6-55277444-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.87

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]

ACMG classification

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	UniProt
HCRTR2	NM_001384272.1	c.827G>A	p.Arg276Gln	missense_variant	5/7	ENST00000370862.4
HCRTR2	NM_001526.5	c.827G>A	p.Arg276Gln	missense_variant	6/8
HCRTR2	XM_017010798.2	c.827G>A	p.Arg276Gln	missense_variant	6/9

Ensembl

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

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461762 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727176

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.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

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	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	18
DANN	Benign	0.97
DEOGEN2	Benign	0.057	T;T
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.075
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.78	T;.
M_CAP	Benign	0.0081	T
MetaRNN	Benign	0.14	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.69	N;N
MutationTaster	Benign	0.59	D
PrimateAI	Benign	0.44	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	D
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

Other links and lift over

dbSNP: rs756748911; hg19: chr6-55142242;