2-11669690-A-G

Position:

• chr2-11669690-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The ENST00000306928.6(NTSR2):​c.440T>C​(p.Leu147Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000507 in 1,380,268 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000051 (0 hom.)
• Consequence: NTSR2 ENST00000306928.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.65

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NTSR2	NM_012344.4	c.440T>C	p.Leu147Pro	missense_variant	1/4	ENST00000306928.6	NP_036476.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NTSR2	ENST00000306928.6	c.440T>C	p.Leu147Pro	missense_variant	1/4	1	NM_012344.4	ENSP00000303686	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000507 AC: 7 AN: 1380268 Hom.: 0 Cov.: 40 AF XY: 0.00000294 AC XY: 2 AN XY: 680774

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000650

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

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

Jun 26, 2023

The c.440T>C (p.L147P) alteration is located in exon 1 (coding exon 1) of the NTSR2 gene. This alteration results from a T to C substitution at nucleotide position 440, causing the leucine (L) at amino acid position 147 to be replaced by a proline (P). 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	0.21
BayesDel_addAF	Benign	-0.046	T
BayesDel_noAF	Benign	-0.30
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.14	T
Eigen	Uncertain	0.34
Eigen_PC	Benign	0.21
FATHMM_MKL	Benign	0.31	N
LIST_S2	Benign	0.61	T
M_CAP	Benign	0.050	D
MetaRNN	Uncertain	0.47	T
MetaSVM	Benign	-0.76	T
MutationAssessor	Benign	1.9	M
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-2.5	N
REVEL	Benign	0.28
Sift	Uncertain	0.012	D
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.21
MutPred		0.71		Gain of disorder (P = 0.0096);
MVP		0.63
MPC		3.2
ClinPred		0.92	D
GERP RS		3.2
Varity_R		0.77
gMVP		0.65

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: rs988038686; hg19: chr2-11809816;