rs45554739

Variant names:

• chr9-84670322-A-G
• rs45554739
• NM_006180.6:c.-372-55A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_006180.6(NTRK2):​c.-372-55A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0534 in 295,420 control chromosomes in the GnomAD database, including 719 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.069 (560 hom., cov: 32)
  • Exomes 𝑓: 0.037 (159 hom.)
• Consequence: NTRK2 NM_006180.6 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.292
• Publications: 1 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 9-84670322-A-G is Benign according to our data. Variant chr9-84670322-A-G is described in ClinVar as [Benign]. Clinvar id is 1246961.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.147 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NTRK2	NM_006180.6	c.-372-55A>G		intron_variant	Intron 1 of 18	ENST00000277120.8	NP_006171.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NTRK2	ENST00000277120.8	c.-372-55A>G		intron_variant	Intron 1 of 18	1	NM_006180.6	ENSP00000277120.3

Frequencies

GnomAD3 genomes AF: 0.0690 AC: 10486 AN: 151926 Hom.: 559 Cov.: 32

Gnomad AFR AF: 0.150

Gnomad AMI AF: 0.120

Gnomad AMR AF: 0.0679

Gnomad ASJ AF: 0.0185

Gnomad EAS AF: 0.0321

Gnomad SAS AF: 0.0158

Gnomad FIN AF: 0.0325

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.0348

Gnomad OTH AF: 0.0617

GnomAD4 exome AF: 0.0368 AC: 5272 AN: 143374 Hom.: 159 AF XY: 0.0353 AC XY: 2464 AN XY: 69768

African (AFR) AF: 0.154 AC: 633 AN: 4118

American (AMR) AF: 0.0620 AC: 344 AN: 5552

Ashkenazi Jewish (ASJ) AF: 0.0238 AC: 147 AN: 6178

East Asian (EAS) AF: 0.0345 AC: 482 AN: 13988

South Asian (SAS) AF: 0.0143 AC: 124 AN: 8678

European-Finnish (FIN) AF: 0.0291 AC: 107 AN: 3674

Middle Eastern (MID) AF: 0.0245 AC: 18 AN: 736

European-Non Finnish (NFE) AF: 0.0329 AC: 2973 AN: 90276

Other (OTH) AF: 0.0436 AC: 444 AN: 10174

GnomAD4 genome AF: 0.0691 AC: 10508 AN: 152046 Hom.: 560 Cov.: 32 AF XY: 0.0676 AC XY: 5028 AN XY: 74324

African (AFR) AF: 0.150 AC: 6208 AN: 41482

American (AMR) AF: 0.0677 AC: 1034 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.0185 AC: 64 AN: 3466

East Asian (EAS) AF: 0.0320 AC: 164 AN: 5130

South Asian (SAS) AF: 0.0162 AC: 78 AN: 4820

European-Finnish (FIN) AF: 0.0325 AC: 344 AN: 10590

Middle Eastern (MID) AF: 0.0544 AC: 16 AN: 294

European-Non Finnish (NFE) AF: 0.0348 AC: 2362 AN: 67964

Other (OTH) AF: 0.0610 AC: 129 AN: 2114

Alfa AF: 0.0569 Hom.: 33

Bravo AF: 0.0767

Asia WGS AF: 0.0330 AC: 113 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jun 20, 2021

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	-0.83
CADD	Benign	4.1
DANN	Benign	0.37
PhyloP100		-0.29
PromoterAI		-0.025	Neutral
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: rs45554739; hg19: chr9-87285237;