rs1473576745

Variant names:

• chr2-11658640-A-G
• rs1473576745
• NM_012344.4:c.1072T>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_012344.4(NTSR2):​c.1072T>C​(p.Tyr358His) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,888 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: NTSR2 NM_012344.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.54
• Publications: 0 publications found

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]

ENSG00000303313 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.934

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012344.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NTSR2	NM_012344.4	MANE Select	c.1072T>C	p.Tyr358His	missense	Exon 4 of 4	NP_036476.2	O95665

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NTSR2	ENST00000306928.6	TSL:1 MANE Select	c.1072T>C	p.Tyr358His	missense	Exon 4 of 4	ENSP00000303686.5	O95665
	NTSR2	ENST00000950908.1		c.1120T>C	p.Tyr374His	missense	Exon 5 of 5	ENSP00000620967.1
	ENSG00000303313	ENST00000793551.1		n.427A>G		non_coding_transcript_exon	Exon 2 of 2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461888 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727244

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112006

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000658 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.48
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.20
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.66	D
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.058	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Pathogenic	0.98	D
MutationAssessor	Pathogenic	3.7	H
PhyloP100		6.5
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-3.9	D
REVEL	Pathogenic	0.65
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.73
MVP		0.90
MPC		0.68
ClinPred		0.99	D
GERP RS		2.8
Varity_R		0.71
gMVP		0.81
Mutation Taster		=79/21	polymorphism

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

Other links and lift over

dbSNP: rs1473576745; hg19: chr2-11798766;