Genetic Variant NTSR2:p.Arg409Gln (chr2-11658486-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_012344.4(NTSR2):c.1226G>A(p.Arg409Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000606 in 1,600,368 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000056 ( 0 hom. )

Consequence

NTSR2
NM_012344.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.473

Variant links:

Genes affected

NTSR2 (HGNC:8040): (neurotensin receptor 2) The protein encoded by this gene belongs to the G protein-coupled receptor family that activate a phosphatidylinositol-calcium second messenger system. Binding and pharmacological studies demonstrate that this receptor binds neurotensin as well as several other ligands already described for neurotensin NT1 receptor. However, unlike NT1 receptor, this gene recognizes, with high affinity, levocabastine, a histamine H1 receptor antagonist previously shown to compete with neurotensin for low-affinity binding sites in brain. These activities suggest that this receptor may be of physiological importance and that a natural agonist for the receptor may exist. [provided by RefSeq, Jul 2008]

NTSR2 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.021257252).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NTSR2	NM_012344.4 link	c.1226G>A	p.Arg409Gln	missense_variant	Exon 4 of 4	ENST00000306928.6	NP_036476.2	O95665

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NTSR2	ENST00000306928.6 link	c.1226G>A	p.Arg409Gln	missense_variant	Exon 4 of 4	1	NM_012344.4	ENSP00000303686.5		O95665

Frequencies

GnomAD3 genomes

AF:

0.000105

AC:

AN:

152198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000524

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000577

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000124

AC:

AN:

242538

Hom.:

AF XY:

0.000153

AC XY:

AN XY:

131100

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000123

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000495

Gnomad SAS exome

AF:

0.000486

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000181

Gnomad OTH exome

AF:

0.000171

GnomAD4 exome

AF:

0.0000559

AC:

AN:

1448052

Hom.:

Cov.:

AF XY:

0.0000626

AC XY:

AN XY:

718896

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000937

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000228

Gnomad4 SAS exome

AF:

0.000331

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000335

Gnomad4 OTH exome

AF:

0.0000335

GnomAD4 genome

AF:

0.000105

AC:

AN:

152316

Hom.:

Cov.:

AF XY:

0.000161

AC XY:

AN XY:

74488

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.000523

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000578

Gnomad4 SAS

AF:

0.000208

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000540

Hom.:

Bravo

AF:

0.0000756

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ExAC

AF:

0.0000659

AC:

Asia WGS

AF:

0.00115

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Sep 09, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1226G>A (p.R409Q) alteration is located in exon 4 (coding exon 4) of the NTSR2 gene. This alteration results from a G to A substitution at nucleotide position 1226, causing the arginine (R) at amino acid position 409 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

0.074

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.54

CADD

Benign

0.42

DANN

Benign

0.71

DEOGEN2

Benign

0.031

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.050

LIST_S2

Benign

0.39

M_CAP

Benign

0.023

MetaRNN

Benign

0.021

MetaSVM

Benign

-0.89

MutationAssessor

Benign

0.0

PrimateAI

Benign

0.26

PROVEAN

Benign

-0.14

REVEL

Benign

0.14

Sift

Benign

0.20

Sift4G

Benign

0.48

Polyphen

0.028

Vest4

0.071

MVP

0.46

MPC

0.16

ClinPred

0.011

GERP RS

-5.8

Varity_R

0.024

gMVP

0.20

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over