rs1078947

Variant names:

• chr9-84948337-T-C
• rs1078947
• NM_006180.6:c.1765-125T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_006180.6(NTRK2):​c.1765-125T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.841 in 990,600 control chromosomes in the GnomAD database, including 351,382 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.82 (50796 hom., cov: 32)
  • Exomes 𝑓: 0.85 (300586 hom.)
• Consequence: NTRK2 NM_006180.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.31
• Publications: 5 publications found

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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 9-84948337-T-C is Benign according to our data. Variant chr9-84948337-T-C is described in ClinVar as [Benign]. Clinvar id is 1235842.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.85 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NTRK2	NM_006180.6	c.1765-125T>C		intron_variant	Intron 15 of 18	ENST00000277120.8	NP_006171.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NTRK2	ENST00000277120.8	c.1765-125T>C		intron_variant	Intron 15 of 18	1	NM_006180.6	ENSP00000277120.3

Frequencies

GnomAD3 genomes AF: 0.816 AC: 124013 AN: 152028 Hom.: 50759 Cov.: 32

Gnomad AFR AF: 0.756

Gnomad AMI AF: 0.895

Gnomad AMR AF: 0.813

Gnomad ASJ AF: 0.870

Gnomad EAS AF: 0.747

Gnomad SAS AF: 0.860

Gnomad FIN AF: 0.785

Gnomad MID AF: 0.813

Gnomad NFE AF: 0.856

Gnomad OTH AF: 0.811

GnomAD4 exome AF: 0.845 AC: 708902 AN: 838454 Hom.: 300586 AF XY: 0.846 AC XY: 368468 AN XY: 435460

African (AFR) AF: 0.752 AC: 15683 AN: 20846

American (AMR) AF: 0.828 AC: 28977 AN: 34976

Ashkenazi Jewish (ASJ) AF: 0.856 AC: 18551 AN: 21664

East Asian (EAS) AF: 0.712 AC: 23622 AN: 33160

South Asian (SAS) AF: 0.865 AC: 58367 AN: 67488

European-Finnish (FIN) AF: 0.796 AC: 33787 AN: 42424

Middle Eastern (MID) AF: 0.834 AC: 3830 AN: 4590

European-Non Finnish (NFE) AF: 0.859 AC: 492977 AN: 573564

Other (OTH) AF: 0.833 AC: 33108 AN: 39742

GnomAD4 genome AF: 0.816 AC: 124103 AN: 152146 Hom.: 50796 Cov.: 32 AF XY: 0.813 AC XY: 60471 AN XY: 74370

African (AFR) AF: 0.756 AC: 31364 AN: 41484

American (AMR) AF: 0.814 AC: 12448 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.870 AC: 3022 AN: 3472

East Asian (EAS) AF: 0.747 AC: 3867 AN: 5174

South Asian (SAS) AF: 0.860 AC: 4144 AN: 4818

European-Finnish (FIN) AF: 0.785 AC: 8311 AN: 10584

Middle Eastern (MID) AF: 0.803 AC: 236 AN: 294

European-Non Finnish (NFE) AF: 0.856 AC: 58189 AN: 67998

Other (OTH) AF: 0.808 AC: 1706 AN: 2112

Alfa AF: 0.842 Hom.: 68453

Bravo AF: 0.815

Asia WGS AF: 0.785 AC: 2730 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.88
DANN	Benign	0.45
PhyloP100		-1.3
Mutation Taster		=100/0	polymorphism (auto)

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: rs1078947; hg19: chr9-87563252; COSMIC: COSV52878124;