9-84832012-G-T

Variant names:

• chr9-84832012-G-T
• rs11140776
• NM_006180.6:c.1397-29028G>T

Variant summary

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

The NM_006180.6(NTRK2):​c.1397-29028G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.5 in 152,028 control chromosomes in the GnomAD database, including 19,175 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 0.50 (19175 hom., cov: 33)
• Consequence: NTRK2 NM_006180.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.110
• Publications: 2 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

LOC124902193 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.549 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NTRK2	NM_006180.6	MANE Select	c.1397-29028G>T		intron	N/A	NP_006171.2
	NTRK2	NM_001018064.3		c.1397-35231G>T		intron	N/A	NP_001018074.1
	NTRK2	NM_001369532.1		c.1397-35231G>T		intron	N/A	NP_001356461.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NTRK2	ENST00000277120.8	TSL:1 MANE Select	c.1397-29028G>T		intron	N/A	ENSP00000277120.3
	NTRK2	ENST00000323115.11	TSL:1	c.1361-35231G>T		intron	N/A	ENSP00000314586.5
	NTRK2	ENST00000304053.11	TSL:1	c.1397-35231G>T		intron	N/A	ENSP00000306167.7

Frequencies

GnomAD3 genomes AF: 0.500 AC: 75891 AN: 151910 Hom.: 19144 Cov.: 33

Gnomad AFR AF: 0.555

Gnomad AMI AF: 0.500

Gnomad AMR AF: 0.509

Gnomad ASJ AF: 0.501

Gnomad EAS AF: 0.334

Gnomad SAS AF: 0.411

Gnomad FIN AF: 0.456

Gnomad MID AF: 0.481

Gnomad NFE AF: 0.490

Gnomad OTH AF: 0.495

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

GnomAD4 genome AF: 0.500 AC: 75974 AN: 152028 Hom.: 19175 Cov.: 33 AF XY: 0.494 AC XY: 36714 AN XY: 74298

African (AFR) AF: 0.555 AC: 23005 AN: 41464

American (AMR) AF: 0.509 AC: 7773 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.501 AC: 1738 AN: 3472

East Asian (EAS) AF: 0.334 AC: 1727 AN: 5172

South Asian (SAS) AF: 0.412 AC: 1987 AN: 4822

European-Finnish (FIN) AF: 0.456 AC: 4804 AN: 10546

Middle Eastern (MID) AF: 0.490 AC: 144 AN: 294

European-Non Finnish (NFE) AF: 0.490 AC: 33286 AN: 67964

Other (OTH) AF: 0.498 AC: 1054 AN: 2116

Alfa AF: 0.493 Hom.: 2376

Bravo AF: 0.505

Asia WGS AF: 0.447 AC: 1553 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	6.3
DANN	Benign	0.80
PhyloP100		-0.11
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: rs11140776; hg19: chr9-87446927;