6-55277539-A-G

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_001384272.1(HCRTR2):​c.922A>G​(p.Ile308Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.813 in 1,613,552 control chromosomes in the GnomAD database, including 534,525 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.84 (54364 hom., cov: 33)
  • Exomes 𝑓: 0.81 (480161 hom.)
• Consequence: HCRTR2 NM_001384272.1 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• 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: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=6.7995734E-7).
• BP6: Variant 6-55277539-A-G is Benign according to our data. Variant chr6-55277539-A-G is described in ClinVar as Benign. ClinVar VariationId is 3059587.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.912 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HCRTR2	NM_001384272.1	c.922A>G	p.Ile308Val	missense_variant	Exon 5 of 7	ENST00000370862.4	NP_001371201.1
HCRTR2	NM_001526.5	c.922A>G	p.Ile308Val	missense_variant	Exon 6 of 8		NP_001517.2
HCRTR2	XM_017010798.2	c.922A>G	p.Ile308Val	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>G	p.Ile308Val	missense_variant	Exon 5 of 7	1	NM_001384272.1	ENSP00000359899.3
HCRTR2	ENST00000615358.4	c.922A>G	p.Ile308Val	missense_variant	Exon 6 of 8	1		ENSP00000477548.1

Frequencies

GnomAD3 genomes AF: 0.843 AC: 128305 AN: 152156 Hom.: 54314 Cov.: 33

Gnomad AFR AF: 0.890

Gnomad AMI AF: 0.930

Gnomad AMR AF: 0.876

Gnomad ASJ AF: 0.888

Gnomad EAS AF: 0.934

Gnomad SAS AF: 0.871

Gnomad FIN AF: 0.818

Gnomad MID AF: 0.921

Gnomad NFE AF: 0.798

Gnomad OTH AF: 0.860

GnomAD2 exomes AF: 0.843 AC: 211479 AN: 250970 AF XY: 0.841

Gnomad AFR exome AF: 0.893

Gnomad AMR exome AF: 0.894

Gnomad ASJ exome AF: 0.893

Gnomad EAS exome AF: 0.944

Gnomad FIN exome AF: 0.813

Gnomad NFE exome AF: 0.799

Gnomad OTH exome AF: 0.838

GnomAD4 exome AF: 0.809 AC: 1182709 AN: 1461278 Hom.: 480161 Cov.: 52 AF XY: 0.812 AC XY: 590104 AN XY: 726970

African (AFR) AF: 0.896 AC: 29976 AN: 33466

American (AMR) AF: 0.892 AC: 39870 AN: 44692

Ashkenazi Jewish (ASJ) AF: 0.893 AC: 23329 AN: 26136

East Asian (EAS) AF: 0.947 AC: 37567 AN: 39666

South Asian (SAS) AF: 0.866 AC: 74716 AN: 86254

European-Finnish (FIN) AF: 0.812 AC: 43388 AN: 53416

Middle Eastern (MID) AF: 0.924 AC: 5327 AN: 5764

European-Non Finnish (NFE) AF: 0.790 AC: 878479 AN: 1111496

Other (OTH) AF: 0.829 AC: 50057 AN: 60388

GnomAD4 genome AF: 0.843 AC: 128415 AN: 152274 Hom.: 54364 Cov.: 33 AF XY: 0.848 AC XY: 63110 AN XY: 74442

African (AFR) AF: 0.890 AC: 37007 AN: 41568

American (AMR) AF: 0.876 AC: 13401 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.888 AC: 3083 AN: 3472

East Asian (EAS) AF: 0.934 AC: 4844 AN: 5184

South Asian (SAS) AF: 0.872 AC: 4210 AN: 4830

European-Finnish (FIN) AF: 0.818 AC: 8665 AN: 10596

Middle Eastern (MID) AF: 0.918 AC: 270 AN: 294

European-Non Finnish (NFE) AF: 0.798 AC: 54278 AN: 68010

Other (OTH) AF: 0.857 AC: 1811 AN: 2114

Alfa AF: 0.815 Hom.: 226302

Bravo AF: 0.849

TwinsUK AF: 0.797 AC: 2955

ALSPAC AF: 0.789 AC: 3040

ESP6500AA AF: 0.884 AC: 3897

ESP6500EA AF: 0.794 AC: 6825

ExAC AF: 0.839 AC: 101840

Asia WGS AF: 0.890 AC: 3095 AN: 3478

EpiCase AF: 0.811

EpiControl AF: 0.806

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

HCRTR2-related disorder Benign:1

Oct 16, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.043
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	18
DANN	Benign	0.77
DEOGEN2	Benign	0.044	T;T
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.14
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.20	T;.
MetaRNN	Benign	6.8e-7	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.98	N;N
PhyloP100		7.6
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	0.49	.;N
REVEL	Benign	0.17
Sift	Benign	1.0	.;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0	B;B
Vest4		0.062
MPC		0.32
ClinPred		0.0091	T
GERP RS		6.1
Varity_R		0.091
gMVP		0.33
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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; COSMIC: COSV63796098;