Genetic Variant ENST00000686259.1:c.-866C>A (chr9-84668501-C-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The ENST00000686259.1(NTRK2):c.-866C>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.803 in 152,202 control chromosomes in the GnomAD database, including 49,132 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.80 ( 49131 hom., cov: 34)

Exomes 𝑓: 0.50 ( 1 hom. )

Consequence

NTRK2
ENST00000686259.1 5_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.0520

Publications

17 publications found

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]

NTRK2 Gene-Disease associations (from GenCC):

developmental and epileptic encephalopathy, 58
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
obesity, hyperphagia, and developmental delay
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
infantile spasms
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
undetermined early-onset epileptic encephalopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

NTRK2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.83).

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.799 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000686259.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	HGVSc	Effect	Exon Rank	Protein	UniProt
NTRK2	NM_001369532.1	c.-866C>A	upstream_gene	N/A	NP_001356461.1	Q16620-1
NTRK2	NM_001369533.1	c.-657C>A	upstream_gene	N/A	NP_001356462.1	Q16620-1
NTRK2	NM_001369537.1	c.-746C>A	upstream_gene	N/A	NP_001356466.1	Q16620-5

Ensembl Transcripts

Gene	Transcript	HGVSc	Effect	Exon Rank	Protein	UniProt
NTRK2	ENST00000686259.1	c.-866C>A	5_prime_UTR	Exon 1 of 19	ENSP00000509743.1	Q16620-1
NTRK2	ENST00000686496.1	c.-1321C>A	5_prime_UTR	Exon 1 of 20	ENSP00000510060.1	Q16620-1
NTRK2	ENST00000692181.1	c.-988C>A	5_prime_UTR	Exon 1 of 20	ENSP00000510619.1	Q16620-1

Frequencies

GnomAD3 genomes

AF:

0.803

AC:

122086

AN:

152078

Hom.:

49093

Cov.:

show subpopulations

Gnomad AFR

AF:

0.795

Gnomad AMI

AF:

0.884

Gnomad AMR

AF:

0.810

Gnomad ASJ

AF:

0.785

Gnomad EAS

AF:

0.794

Gnomad SAS

AF:

0.752

Gnomad FIN

AF:

0.835

Gnomad MID

AF:

0.791

Gnomad NFE

AF:

0.805

Gnomad OTH

AF:

0.813

GnomAD4 exome

AF:

0.500

AC:

AN:

Hom.:

Cov.:

AF XY:

0.500

AC XY:

AN XY:

show subpopulations

African (AFR)

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.500

AC:

AN:

Other (OTH)

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.400

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.803

AC:

122181

AN:

152194

Hom.:

49131

Cov.:

AF XY:

0.803

AC XY:

59786

AN XY:

74408

show subpopulations

African (AFR)

AF:

0.795

AC:

33038

AN:

41552

American (AMR)

AF:

0.810

AC:

12401

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.785

AC:

2727

AN:

3472

East Asian (EAS)

AF:

0.794

AC:

4075

AN:

5134

South Asian (SAS)

AF:

0.752

AC:

3632

AN:

4828

European-Finnish (FIN)

AF:

0.835

AC:

8856

AN:

10606

Middle Eastern (MID)

AF:

0.779

AC:

229

AN:

294

European-Non Finnish (NFE)

AF:

0.805

AC:

54704

AN:

67978

Other (OTH)

AF:

0.810

AC:

1713

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1300

2600

3899

5199

6499

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

876

1752

2628

3504

4380

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.797

Hom.:

21431

Bravo

AF:

0.801

Asia WGS

AF:

0.750

AC:

2610

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

(source)

DANN

Benign

0.79

PhyloP100

-0.052

PromoterAI

0.085

Neutral

(source)

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over