2-11662020-C-T

Position:

• chr2-11662020-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000306928.6(NTSR2):​c.845G>A​(p.Arg282Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00432 in 1,612,804 control chromosomes in the GnomAD database, including 232 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.023 (136 hom., cov: 33)
  • Exomes 𝑓: 0.0024 (96 hom.)
• Consequence: NTSR2 ENST00000306928.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.65

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0029715598).
• BP6: Variant 2-11662020-C-T is Benign according to our data. Variant chr2-11662020-C-T is described in ClinVar as [Benign]. Clinvar id is 782401.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0741 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NTSR2	NM_012344.4	c.845G>A	p.Arg282Lys	missense_variant	2/4	ENST00000306928.6	NP_036476.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NTSR2	ENST00000306928.6	c.845G>A	p.Arg282Lys	missense_variant	2/4	1	NM_012344.4	ENSP00000303686	P1

Frequencies

GnomAD3 genomes AF: 0.0226 AC: 3441 AN: 152206 Hom.: 136 Cov.: 33

Gnomad AFR AF: 0.0765

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0118

Gnomad ASJ AF: 0.00951

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000353

Gnomad OTH AF: 0.0153

GnomAD3 exomes AF: 0.00638 AC: 1595 AN: 250040 Hom.: 57 AF XY: 0.00469 AC XY: 634 AN XY: 135148

Gnomad AFR exome AF: 0.0797

Gnomad AMR exome AF: 0.00453

Gnomad ASJ exome AF: 0.00828

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000230

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000291

Gnomad OTH exome AF: 0.00412

GnomAD4 exome AF: 0.00242 AC: 3528 AN: 1460480 Hom.: 96 Cov.: 31 AF XY: 0.00213 AC XY: 1547 AN XY: 726464

Gnomad4 AFR exome AF: 0.0737

Gnomad4 AMR exome AF: 0.00561

Gnomad4 ASJ exome AF: 0.00755

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000186

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000209

Gnomad4 OTH exome AF: 0.00573

GnomAD4 genome AF: 0.0226 AC: 3446 AN: 152324 Hom.: 136 Cov.: 33 AF XY: 0.0219 AC XY: 1633 AN XY: 74488

Gnomad4 AFR AF: 0.0764

Gnomad4 AMR AF: 0.0118

Gnomad4 ASJ AF: 0.00951

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000353

Gnomad4 OTH AF: 0.0151

Alfa AF: 0.00458 Hom.: 35

Bravo AF: 0.0271

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.0715 AC: 315

ESP6500EA AF: 0.000930 AC: 8

ExAC AF: 0.00790 AC: 959

Asia WGS AF: 0.00664 AC: 24 AN: 3478

EpiCase AF: 0.000491

EpiControl AF: 0.000238

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Apr 04, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.039	T
Eigen	Benign	-0.12
Eigen_PC	Benign	-0.21
FATHMM_MKL	Benign	0.50	N
LIST_S2	Benign	0.59	T
MetaRNN	Benign	0.0030	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Uncertain	2.1	M
MutationTaster	Benign	0.99	N
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-0.58	N
REVEL	Benign	0.25
Sift	Benign	0.81	T
Sift4G	Benign	0.55	T
Polyphen		0.98	D
Vest4		0.34
MVP		0.84
MPC		0.63
ClinPred		0.046	T
GERP RS		1.2
Varity_R		0.10
gMVP		0.27

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs34764121; hg19: chr2-11802146;