chr9-85002053-A-G

Variant names:

• chr9-85002053-A-G
• rs1565446
• NM_006180.6:c.2173-18153A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_006180.6(NTRK2):​c.2173-18153A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.731 in 152,050 control chromosomes in the GnomAD database, including 41,267 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 0.73 (41267 hom., cov: 32)
• Consequence: NTRK2 NM_006180.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.04
• 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.812 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NTRK2	NM_006180.6	MANE Select	c.2173-18153A>G		intron	N/A	NP_006171.2
	NTRK2	NM_001018064.3		c.2125-18153A>G		intron	N/A	NP_001018074.1
	NTRK2	NM_001369532.1		c.2125-18153A>G		intron	N/A	NP_001356461.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NTRK2	ENST00000277120.8	TSL:1 MANE Select	c.2173-18153A>G		intron	N/A	ENSP00000277120.3
	NTRK2	ENST00000323115.11	TSL:1	c.2089-18153A>G		intron	N/A	ENSP00000314586.5
	NTRK2	ENST00000686324.1		c.2173-18153A>G		intron	N/A	ENSP00000510134.1

Frequencies

GnomAD3 genomes AF: 0.731 AC: 111047 AN: 151932 Hom.: 41229 Cov.: 32

Gnomad AFR AF: 0.820

Gnomad AMI AF: 0.776

Gnomad AMR AF: 0.746

Gnomad ASJ AF: 0.744

Gnomad EAS AF: 0.383

Gnomad SAS AF: 0.703

Gnomad FIN AF: 0.592

Gnomad MID AF: 0.804

Gnomad NFE AF: 0.721

Gnomad OTH AF: 0.744

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.731 AC: 111143 AN: 152050 Hom.: 41267 Cov.: 32 AF XY: 0.721 AC XY: 53602 AN XY: 74320

African (AFR) AF: 0.820 AC: 34015 AN: 41504

American (AMR) AF: 0.746 AC: 11406 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.744 AC: 2582 AN: 3470

East Asian (EAS) AF: 0.383 AC: 1973 AN: 5156

South Asian (SAS) AF: 0.703 AC: 3387 AN: 4820

European-Finnish (FIN) AF: 0.592 AC: 6240 AN: 10538

Middle Eastern (MID) AF: 0.796 AC: 234 AN: 294

European-Non Finnish (NFE) AF: 0.721 AC: 49032 AN: 67964

Other (OTH) AF: 0.744 AC: 1566 AN: 2106

Alfa AF: 0.736 Hom.: 7174

Bravo AF: 0.741

Asia WGS AF: 0.629 AC: 2188 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	4.5
DANN	Benign	0.35
PhyloP100		1.0
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: rs1565446; hg19: chr9-87616968;