6-55277447-G-T

Position:

• chr6-55277447-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001384272.1(HCRTR2):​c.830G>T​(p.Gly277Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 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: not found (cov: 33)
• Consequence: HCRTR2 NM_001384272.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.70

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3238089).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HCRTR2	NM_001384272.1	c.830G>T	p.Gly277Val	missense_variant	5/7	ENST00000370862.4	NP_001371201.1
HCRTR2	NM_001526.5	c.830G>T	p.Gly277Val	missense_variant	6/8		NP_001517.2
HCRTR2	XM_017010798.2	c.830G>T	p.Gly277Val	missense_variant	6/9		XP_016866287.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HCRTR2	ENST00000370862.4	c.830G>T	p.Gly277Val	missense_variant	5/7	1	NM_001384272.1	ENSP00000359899.3
HCRTR2	ENST00000615358.4	c.830G>T	p.Gly277Val	missense_variant	6/8	1		ENSP00000477548.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

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

Oct 07, 2024

The c.830G>T (p.G277V) alteration is located in exon 5 (coding exon 5) of the HCRTR2 gene. This alteration results from a G to T substitution at nucleotide position 830, causing the glycine (G) at amino acid position 277 to be replaced by a valine (V). 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	0.072
BayesDel_addAF	Benign	-0.014	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.17	T;T
Eigen	Benign	0.17
Eigen_PC	Benign	0.14
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.78	T;.
M_CAP	Benign	0.025	D
MetaRNN	Benign	0.32	T;T
MetaSVM	Benign	-0.77	T
MutationAssessor	Benign	1.6	L;L
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-1.8	.;N
REVEL	Benign	0.19
Sift	Uncertain	0.0060	.;D
Sift4G	Uncertain	0.013	D;D
Polyphen		0.85	P;P
Vest4		0.28
MutPred		0.31		Loss of glycosylation at P278 (P = 0.0657);Loss of glycosylation at P278 (P = 0.0657);
MVP		0.89
MPC		0.51
ClinPred		0.75	D
GERP RS		4.0
Varity_R		0.26
gMVP		0.55

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-55142245;