9-84752019-G-T

Variant names:

• chr9-84752019-G-T
• rs1085308029
• NM_006180.6:c.1330G>T

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_006180.6(NTRK2):​c.1330G>T​(p.Gly444*) variant causes a stop gained change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. G444G) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NTRK2 NM_006180.6 stop_gained
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 4.01
• 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: Labcorp Genetics (formerly Invitae), G2P
• 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: Pathogenic. The variant received 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 9-84752019-G-T is Pathogenic according to our data. Variant chr9-84752019-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 427213.Status of the report is no_assertion_criteria_provided, 0 stars.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NTRK2	NM_006180.6	MANE Select	c.1330G>T	p.Gly444*	stop_gained	Exon 12 of 19	NP_006171.2
	NTRK2	NM_001018064.3		c.1330G>T	p.Gly444*	stop_gained	Exon 12 of 18	NP_001018074.1	Q548C2
	NTRK2	NM_001369532.1		c.1330G>T	p.Gly444*	stop_gained	Exon 13 of 19	NP_001356461.1	Q16620-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NTRK2	ENST00000277120.8	TSL:1 MANE Select	c.1330G>T	p.Gly444*	stop_gained	Exon 12 of 19	ENSP00000277120.3	Q16620-4
	NTRK2	ENST00000323115.11	TSL:1	c.1294G>T	p.Gly432*	stop_gained	Exon 11 of 17	ENSP00000314586.5	A0A8J8YUT9
	NTRK2	ENST00000304053.11	TSL:1	c.1330G>T	p.Gly444*	stop_gained	Exon 11 of 13	ENSP00000306167.7	Q16620-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Obesity, hyperphagia, and developmental delay (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.52
CADD	Pathogenic	39
DANN	Uncertain	0.99
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.99
FATHMM_MKL	Benign	0.73	D
PhyloP100		4.0
Vest4		0.79
GERP RS		5.2
Mutation Taster		=1/199	disease causing (ClinVar)

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: rs1085308029; hg19: chr9-87366934;