NM_006180.6:c.1765-7T>C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_006180.6(NTRK2):c.1765-7T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0495 in 1,613,678 control chromosomes in the GnomAD database, including 2,691 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.053 ( 299 hom., cov: 32)

Exomes 𝑓: 0.049 ( 2392 hom. )

Consequence

NTRK2
NM_006180.6 splice_region, intron

Scores

Splicing: ADA: 0.0001185

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -0.818

Publications

21 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: G2P, Labcorp Genetics (formerly Invitae)
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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.87).

BP6

Variant 9-84948455-T-C is Benign according to our data. Variant chr9-84948455-T-C is described in ClinVar as Benign. ClinVar VariationId is 1279330.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.119 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006180.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
NTRK2	NM_006180.6	MANE Select	c.1765-7T>C	splice_region intron	N/A	NP_006171.2
NTRK2	NM_001018064.3		c.1717-7T>C	splice_region intron	N/A	NP_001018074.1
NTRK2	NM_001369532.1		c.1717-7T>C	splice_region intron	N/A	NP_001356461.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
NTRK2	ENST00000277120.8	TSL:1 MANE Select	c.1765-7T>C	splice_region intron	N/A	ENSP00000277120.3
NTRK2	ENST00000323115.11	TSL:1	c.1681-7T>C	splice_region intron	N/A	ENSP00000314586.5
NTRK2	ENST00000686324.1		c.1765-7T>C	splice_region intron	N/A	ENSP00000510134.1

Frequencies

GnomAD3 genomes

AF:

0.0531

AC:

8076

AN:

152066

Hom.:

297

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0483

Gnomad AMI

AF:

0.0121

Gnomad AMR

AF:

0.116

Gnomad ASJ

AF:

0.0251

Gnomad EAS

AF:

0.127

Gnomad SAS

AF:

0.0641

Gnomad FIN

AF:

0.0180

Gnomad MID

AF:

0.0443

Gnomad NFE

AF:

0.0428

Gnomad OTH

AF:

0.0556

GnomAD2 exomes

AF:

0.0652

AC:

16342

AN:

250804

AF XY:

0.0605

show subpopulations

Gnomad AFR exome

AF:

0.0488

Gnomad AMR exome

AF:

0.171

Gnomad ASJ exome

AF:

0.0215

Gnomad EAS exome

AF:

0.124

Gnomad FIN exome

AF:

0.0174

Gnomad NFE exome

AF:

0.0421

Gnomad OTH exome

AF:

0.0575

GnomAD4 exome

AF:

0.0491

AC:

71787

AN:

1461494

Hom.:

2392

Cov.:

AF XY:

0.0485

AC XY:

35256

AN XY:

727052

show subpopulations

African (AFR)

AF:

0.0450

AC:

1506

AN:

33476

American (AMR)

AF:

0.166

AC:

7414

AN:

44672

Ashkenazi Jewish (ASJ)

AF:

0.0217

AC:

567

AN:

26132

East Asian (EAS)

AF:

0.120

AC:

4777

AN:

39690

South Asian (SAS)

AF:

0.0517

AC:

4461

AN:

86224

European-Finnish (FIN)

AF:

0.0165

AC:

883

AN:

53400

Middle Eastern (MID)

AF:

0.0329

AC:

190

AN:

5768

European-Non Finnish (NFE)

AF:

0.0439

AC:

48808

AN:

1111756

Other (OTH)

AF:

0.0527

AC:

3181

AN:

60376

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

3441

6881

10322

13762

17203

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1952

3904

5856

7808

9760

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0531

AC:

8083

AN:

152184

Hom.:

299

Cov.:

AF XY:

0.0534

AC XY:

3977

AN XY:

74416

show subpopulations

African (AFR)

AF:

0.0483

AC:

2004

AN:

41524

American (AMR)

AF:

0.116

AC:

1779

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.0251

AC:

AN:

3472

East Asian (EAS)

AF:

0.127

AC:

659

AN:

5170

South Asian (SAS)

AF:

0.0635

AC:

306

AN:

4818

European-Finnish (FIN)

AF:

0.0180

AC:

191

AN:

10604

Middle Eastern (MID)

AF:

0.0408

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0429

AC:

2914

AN:

68004

Other (OTH)

AF:

0.0569

AC:

120

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

388

775

1163

1550

1938

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

184

276

368

460

<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:

0.0484

Hom.:

847

Bravo

AF:

0.0616

Asia WGS

AF:

0.118

AC:

411

AN:

3478

EpiCase

AF:

0.0439

EpiControl

AF:

0.0412

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Sep 04, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.87

CADD

Benign

0.66

(source)

DANN

Benign

0.44

PhyloP100

-0.82

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00012

dbscSNV1_RF

Benign

0.022

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

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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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over