rs2653349

Variant names:

• chr6-55277539-A-C
• rs2653349
• NM_001384272.1:c.922A>C

Your query was ambiguous. Multiple possible variants found:

• chr6-55277539-A-C
• chr6-55277539-A-G
• chr6-55277539-A-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001384272.1(HCRTR2):​c.922A>C​(p.Ile308Leu) 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)
• Consequence: HCRTR2 NM_001384272.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.56
• Publications: 74 publications found

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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21384549).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HCRTR2	NM_001384272.1	c.922A>C	p.Ile308Leu	missense_variant	Exon 5 of 7	ENST00000370862.4	NP_001371201.1
HCRTR2	NM_001526.5	c.922A>C	p.Ile308Leu	missense_variant	Exon 6 of 8		NP_001517.2
HCRTR2	XM_017010798.2	c.922A>C	p.Ile308Leu	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	c.922A>C	p.Ile308Leu	missense_variant	Exon 5 of 7	1	NM_001384272.1	ENSP00000359899.3
HCRTR2	ENST00000615358.4	c.922A>C	p.Ile308Leu	missense_variant	Exon 6 of 8	1		ENSP00000477548.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 52

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.39
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.099	T;T
Eigen	Benign	-0.17
Eigen_PC	Benign	0.074
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.84	T;.
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.21	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.55	N;N
PhyloP100		7.6
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-0.91	.;N
REVEL	Benign	0.19
Sift	Benign	0.041	.;D
Sift4G	Benign	0.40	T;T
Polyphen		0.0	B;B
Vest4		0.26
MutPred		0.57		Loss of MoRF binding (P = 0.1188);Loss of MoRF binding (P = 0.1188);
MVP		0.74
MPC		0.39
ClinPred		0.83	D
GERP RS		6.1
Varity_R		0.27
gMVP		0.68
Mutation Taster		=92/8	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2653349; hg19: chr6-55142337;