rs1490403

Variant names:

• chr9-85023591-T-A
• rs1490403
• NM_006180.6:c.*2154T>A

Variant summary

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

The NM_006180.6(NTRK2):​c.*2154T>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.714 in 224,384 control chromosomes in the GnomAD database, including 58,903 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 0.74 (41976 hom., cov: 28)
  • Exomes 𝑓: 0.67 (16927 hom.)
• Consequence: NTRK2 NM_006180.6 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.397
• Publications: 4 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=-0.88).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.835 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NTRK2	NM_006180.6	c.*2154T>A		3_prime_UTR_variant	Exon 19 of 19	ENST00000277120.8	NP_006171.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NTRK2	ENST00000277120.8	c.*2154T>A		3_prime_UTR_variant	Exon 19 of 19	1	NM_006180.6	ENSP00000277120.3

Frequencies

GnomAD3 genomes AF: 0.737 AC: 111702 AN: 151578 Hom.: 41932 Cov.: 28

Gnomad AFR AF: 0.843

Gnomad AMI AF: 0.769

Gnomad AMR AF: 0.745

Gnomad ASJ AF: 0.720

Gnomad EAS AF: 0.378

Gnomad SAS AF: 0.707

Gnomad FIN AF: 0.590

Gnomad MID AF: 0.791

Gnomad NFE AF: 0.723

Gnomad OTH AF: 0.739

GnomAD4 exome AF: 0.666 AC: 48416 AN: 72688 Hom.: 16927 Cov.: 0 AF XY: 0.668 AC XY: 22407 AN XY: 33540

African (AFR) AF: 0.840 AC: 2826 AN: 3366

American (AMR) AF: 0.740 AC: 1608 AN: 2174

Ashkenazi Jewish (ASJ) AF: 0.728 AC: 3351 AN: 4606

East Asian (EAS) AF: 0.313 AC: 3371 AN: 10782

South Asian (SAS) AF: 0.703 AC: 446 AN: 634

European-Finnish (FIN) AF: 0.500 AC: 27 AN: 54

Middle Eastern (MID) AF: 0.779 AC: 338 AN: 434

European-Non Finnish (NFE) AF: 0.720 AC: 32140 AN: 44618

Other (OTH) AF: 0.716 AC: 4309 AN: 6020

GnomAD4 genome AF: 0.737 AC: 111804 AN: 151696 Hom.: 41976 Cov.: 28 AF XY: 0.727 AC XY: 53840 AN XY: 74100

African (AFR) AF: 0.843 AC: 34852 AN: 41350

American (AMR) AF: 0.745 AC: 11356 AN: 15244

Ashkenazi Jewish (ASJ) AF: 0.720 AC: 2499 AN: 3470

East Asian (EAS) AF: 0.377 AC: 1945 AN: 5154

South Asian (SAS) AF: 0.707 AC: 3369 AN: 4766

European-Finnish (FIN) AF: 0.590 AC: 6178 AN: 10470

Middle Eastern (MID) AF: 0.779 AC: 229 AN: 294

European-Non Finnish (NFE) AF: 0.723 AC: 49121 AN: 67936

Other (OTH) AF: 0.740 AC: 1554 AN: 2100

Alfa AF: 0.732 Hom.: 5081

Bravo AF: 0.748

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.28
DANN	Benign	0.28
PhyloP100		0.40
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1490403; hg19: chr9-87638506;