rs41271310

chr6-55174615-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Strong BP6_Moderate

The NM_001384272.1(HCRTR2):c.28C>T(p.Pro10Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00296 in 1,614,038 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Synonymous variant affecting the same amino acid position (i.e. P10P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0019 (1 hom., cov: 30)
  • Exomes 𝑓: 0.0031 (12 hom.)
• Consequence: HCRTR2 NM_001384272.1 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 4.26

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0052185953).
• BP6: Variant 6-55174615-C-T is Benign according to our data. Variant chr6-55174615-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 3042775.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HCRTR2	NM_001384272.1	c.28C>T	p.Pro10Ser	missense_variant	1/7	ENST00000370862.4
HCRTR2	NM_001526.5	c.28C>T	p.Pro10Ser	missense_variant	2/8
HCRTR2	XM_017010798.2	c.28C>T	p.Pro10Ser	missense_variant	2/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HCRTR2	ENST00000370862.4	c.28C>T	p.Pro10Ser	missense_variant	1/7	1	NM_001384272.1	P1
HCRTR2	ENST00000615358.4	c.28C>T	p.Pro10Ser	missense_variant	2/8	1		P1

Frequencies

GnomAD3 genomes AF: 0.00193 AC: 294 AN: 152060 Hom.: 1 Cov.: 30

Gnomad AFR AF: 0.000435

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00164

Gnomad ASJ AF: 0.00230

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00415

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00316

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00250 AC: 628 AN: 251364 Hom.: 1 AF XY: 0.00278 AC XY: 377 AN XY: 135848

Gnomad AFR exome AF: 0.000431

Gnomad AMR exome AF: 0.00116

Gnomad ASJ exome AF: 0.00109

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00516

Gnomad FIN exome AF: 0.000647

Gnomad NFE exome AF: 0.00339

Gnomad OTH exome AF: 0.00212

GnomAD4 exome AF: 0.00306 AC: 4478 AN: 1461860 Hom.: 12 Cov.: 31 AF XY: 0.00311 AC XY: 2260 AN XY: 727238

Gnomad4 AFR exome AF: 0.000448

Gnomad4 AMR exome AF: 0.00116

Gnomad4 ASJ exome AF: 0.00180

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00561

Gnomad4 FIN exome AF: 0.000505

Gnomad4 NFE exome AF: 0.00331

Gnomad4 OTH exome AF: 0.00263

GnomAD4 genome AF: 0.00193 AC: 294 AN: 152178 Hom.: 1 Cov.: 30 AF XY: 0.00196 AC XY: 146 AN XY: 74388

Gnomad4 AFR AF: 0.000433

Gnomad4 AMR AF: 0.00164

Gnomad4 ASJ AF: 0.00230

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00416

Gnomad4 FIN AF: 0.000377

Gnomad4 NFE AF: 0.00316

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00302 Hom.: 1

Bravo AF: 0.00187

TwinsUK AF: 0.00405 AC: 15

ALSPAC AF: 0.00285 AC: 11

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00314 AC: 27

ExAC AF: 0.00261 AC: 317

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.00289

EpiControl AF: 0.00308

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

HCRTR2-related condition Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 09, 2022

This variant is classified as likely 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	0.063
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.13
Cadd	Benign	19
Dann	Uncertain	0.98
DEOGEN2	Benign	0.055	T;T
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.26
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.77	T;.
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.0052	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L;L
MutationTaster	Benign	0.95	N
PrimateAI	Benign	0.30	T
Sift4G	Benign	0.087	T;T
Polyphen		0.0010	B;B
Vest4		0.74
MVP		0.72
MPC		0.39
ClinPred		0.027	T
GERP RS		4.1
Varity_R		0.098
gMVP		0.50

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: rs41271310; hg19: chr6-55039413; COSMIC: COSV99057007;