rs1373336521

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP6BS2

The NM_006180.6(NTRK2):​c.25G>A​(p.Gly9Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000744 in 1,613,598 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

NTRK2
NM_006180.6 missense

Scores

4
7
8

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:1

Conservation

PhyloP100: 3.55
Variant links:
Genes affected
NTRK2 (HGNC:8032): (neurotrophic receptor tyrosine kinase 2) This gene encodes a member of the neurotrophic tyrosine receptor kinase (NTRK) family. This kinase is a membrane-bound receptor that, upon neurotrophin binding, phosphorylates itself and members of the MAPK pathway. Signalling through this kinase leads to cell differentiation. Mutations in this gene have been associated with obesity and mood disorders. Alternative splicing results in multiple transcript variants. [provided by RefSeq, May 2014]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP6
Variant 9-84670773-G-A is Benign according to our data. Variant chr9-84670773-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1341751.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=1}.
BS2
High AC in GnomAd4 at 5 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
NTRK2NM_006180.6 linkc.25G>A p.Gly9Arg missense_variant Exon 2 of 19 ENST00000277120.8 NP_006171.2 Q16620-4A0A024R230Q5VWE5

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
NTRK2ENST00000277120.8 linkc.25G>A p.Gly9Arg missense_variant Exon 2 of 19 1 NM_006180.6 ENSP00000277120.3 Q16620-4

Frequencies

GnomAD3 genomes
AF:
0.0000328
AC:
5
AN:
152250
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000196
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.000478
GnomAD4 exome
AF:
0.00000479
AC:
7
AN:
1461348
Hom.:
0
Cov.:
33
AF XY:
0.00000550
AC XY:
4
AN XY:
726980
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000447
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:
0.00000270
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.0000328
AC:
5
AN:
152250
Hom.:
0
Cov.:
33
AF XY:
0.0000538
AC XY:
4
AN XY:
74380
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.000196
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.000478
Bravo
AF:
0.000102

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:3Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

NTRK2-related disorder Uncertain:1
Apr 10, 2024
PreventionGenetics, part of Exact Sciences
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: clinical testing

The NTRK2 c.25G>A variant is predicted to result in the amino acid substitution p.Gly9Arg. To our knowledge, this variant has not been reported in the literature or in a large population database, indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Inborn genetic diseases Uncertain:1
Aug 20, 2023
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.25G>A (p.G9R) alteration is located in exon 4 (coding exon 1) of the NTRK2 gene. This alteration results from a G to A substitution at nucleotide position 25, causing the glycine (G) at amino acid position 9 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Developmental and epileptic encephalopathy, 58 Uncertain:1
Jan 15, 2021
New York Genome Center
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not provided Benign:1
Jan 20, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.16
BayesDel_addAF
Pathogenic
0.33
D
BayesDel_noAF
Pathogenic
0.23
CADD
Pathogenic
26
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.41
.;T;.;.;.;.;T;.
Eigen
Uncertain
0.55
Eigen_PC
Uncertain
0.58
FATHMM_MKL
Uncertain
0.89
D
LIST_S2
Uncertain
0.91
D;D;D;D;D;.;.;.
M_CAP
Pathogenic
0.32
D
MetaRNN
Uncertain
0.45
T;T;T;T;T;T;T;T
MetaSVM
Benign
-0.30
T
MutationAssessor
Benign
1.1
L;L;L;L;L;L;L;L
PrimateAI
Uncertain
0.56
T
PROVEAN
Benign
-1.8
N;N;N;N;N;N;N;N
REVEL
Uncertain
0.46
Sift
Benign
0.045
D;D;D;D;D;D;D;D
Sift4G
Benign
0.25
T;T;D;D;D;T;T;D
Polyphen
1.0
D;D;D;D;D;D;D;D
Vest4
0.29
MutPred
0.43
Loss of catalytic residue at G9 (P = 0.0639);Loss of catalytic residue at G9 (P = 0.0639);Loss of catalytic residue at G9 (P = 0.0639);Loss of catalytic residue at G9 (P = 0.0639);Loss of catalytic residue at G9 (P = 0.0639);Loss of catalytic residue at G9 (P = 0.0639);Loss of catalytic residue at G9 (P = 0.0639);Loss of catalytic residue at G9 (P = 0.0639);
MVP
0.92
MPC
1.7
ClinPred
0.94
D
GERP RS
5.0
Varity_R
0.28
gMVP
0.78

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.

Other links and lift over

dbSNP: rs1373336521; hg19: chr9-87285688; API