NM_006180.6:c.2172+3545A>G

Variant names:

• chr9-84959062-A-G
• rs2277192
• NM_006180.6:c.2172+3545A>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.2172+3545A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.121 in 152,180 control chromosomes in the GnomAD database, including 1,541 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 0.12 (1541 hom., cov: 32)
• Consequence: NTRK2 NM_006180.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.205
• Publications: 11 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=-0.91).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.369 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.2172+3545A>G		intron	N/A	NP_006171.2
	NTRK2	NM_001018064.3		c.2124+3545A>G		intron	N/A	NP_001018074.1
	NTRK2	NM_001369532.1		c.2124+3545A>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.2172+3545A>G		intron	N/A	ENSP00000277120.3
	NTRK2	ENST00000323115.11	TSL:1	c.2088+3545A>G		intron	N/A	ENSP00000314586.5
	NTRK2	ENST00000686324.1		c.2172+3545A>G		intron	N/A	ENSP00000510134.1

Frequencies

GnomAD3 genomes AF: 0.121 AC: 18429 AN: 152062 Hom.: 1540 Cov.: 32

Gnomad AFR AF: 0.0402

Gnomad AMI AF: 0.135

Gnomad AMR AF: 0.119

Gnomad ASJ AF: 0.0904

Gnomad EAS AF: 0.382

Gnomad SAS AF: 0.109

Gnomad FIN AF: 0.160

Gnomad MID AF: 0.108

Gnomad NFE AF: 0.147

Gnomad OTH AF: 0.121

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

GnomAD4 genome AF: 0.121 AC: 18431 AN: 152180 Hom.: 1541 Cov.: 32 AF XY: 0.122 AC XY: 9080 AN XY: 74396

African (AFR) AF: 0.0401 AC: 1667 AN: 41536

American (AMR) AF: 0.119 AC: 1821 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0904 AC: 314 AN: 3472

East Asian (EAS) AF: 0.383 AC: 1969 AN: 5140

South Asian (SAS) AF: 0.109 AC: 525 AN: 4816

European-Finnish (FIN) AF: 0.160 AC: 1700 AN: 10598

Middle Eastern (MID) AF: 0.119 AC: 35 AN: 294

European-Non Finnish (NFE) AF: 0.147 AC: 10023 AN: 68004

Other (OTH) AF: 0.120 AC: 254 AN: 2116

Alfa AF: 0.138 Hom.: 3147

Bravo AF: 0.118

Asia WGS AF: 0.214 AC: 746 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.60
DANN	Benign	0.47
PhyloP100		-0.20
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: rs2277192; hg19: chr9-87573977; COSMIC: COSV52858218;