ENST00000359847.4:c.*804A>G

Variant names:

• chr9-84811383-A-G
• rs2013566
• ENST00000359847.4:c.*804A>G

Variant summary

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

The ENST00000359847.4(NTRK2):​c.*804A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.105 in 1,065,824 control chromosomes in the GnomAD database, including 8,419 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 0.17 (3441 hom., cov: 32)
  • Exomes 𝑓: 0.093 (4978 hom.)
• Consequence: NTRK2 ENST00000359847.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.286
• Publications: 17 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.357 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000359847.4. 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.1397-49657A>G		intron	N/A	NP_006171.2
	NTRK2	NM_001007097.3		c.*804A>G		3_prime_UTR	Exon 15 of 15	NP_001007098.1	Q16620-2
	NTRK2	NM_001369539.1		c.*804A>G		3_prime_UTR	Exon 13 of 13	NP_001356468.1	Q16620-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NTRK2	ENST00000359847.4	TSL:1	c.*804A>G		3_prime_UTR	Exon 14 of 14	ENSP00000352906.3	Q16620-2
	NTRK2	ENST00000395882.6	TSL:1	c.*804A>G		3_prime_UTR	Exon 15 of 15	ENSP00000379221.1	Q16620-2
	NTRK2	ENST00000277120.8	TSL:1 MANE Select	c.1397-49657A>G		intron	N/A	ENSP00000277120.3	Q16620-4

Frequencies

GnomAD3 genomes AF: 0.173 AC: 26360 AN: 152070 Hom.: 3432 Cov.: 32

Gnomad AFR AF: 0.362

Gnomad AMI AF: 0.139

Gnomad AMR AF: 0.180

Gnomad ASJ AF: 0.0975

Gnomad EAS AF: 0.172

Gnomad SAS AF: 0.117

Gnomad FIN AF: 0.0766

Gnomad MID AF: 0.139

Gnomad NFE AF: 0.0815

Gnomad OTH AF: 0.151

GnomAD4 exome AF: 0.0934 AC: 85295 AN: 913636 Hom.: 4978 Cov.: 33 AF XY: 0.0925 AC XY: 39001 AN XY: 421726

African (AFR) AF: 0.373 AC: 7334 AN: 19654

American (AMR) AF: 0.159 AC: 552 AN: 3474

Ashkenazi Jewish (ASJ) AF: 0.100 AC: 1029 AN: 10246

East Asian (EAS) AF: 0.168 AC: 2509 AN: 14940

South Asian (SAS) AF: 0.102 AC: 1758 AN: 17154

European-Finnish (FIN) AF: 0.0654 AC: 34 AN: 520

Middle Eastern (MID) AF: 0.121 AC: 256 AN: 2110

European-Non Finnish (NFE) AF: 0.0837 AC: 67921 AN: 811510

Other (OTH) AF: 0.115 AC: 3902 AN: 34028

GnomAD4 genome AF: 0.174 AC: 26412 AN: 152188 Hom.: 3441 Cov.: 32 AF XY: 0.173 AC XY: 12909 AN XY: 74418

African (AFR) AF: 0.362 AC: 15015 AN: 41466

American (AMR) AF: 0.179 AC: 2746 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0975 AC: 338 AN: 3468

East Asian (EAS) AF: 0.172 AC: 890 AN: 5180

South Asian (SAS) AF: 0.117 AC: 567 AN: 4828

European-Finnish (FIN) AF: 0.0766 AC: 812 AN: 10602

Middle Eastern (MID) AF: 0.136 AC: 40 AN: 294

European-Non Finnish (NFE) AF: 0.0816 AC: 5548 AN: 68022

Other (OTH) AF: 0.156 AC: 329 AN: 2112

Alfa AF: 0.106 Hom.: 2062

Bravo AF: 0.189

Asia WGS AF: 0.176 AC: 611 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	1.1
DANN	Benign	0.55
PhyloP100		-0.29
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: rs2013566; hg19: chr9-87426298;