9-84814375-A-T

Variant names:

• chr9-84814375-A-T
• rs1624327
• ENST00000359847.4:c.*3796A>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 2P and 8B. PM2 BP4_Strong BS2

The NM_001007097.3(NTRK2):​c.*3796A>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000548 in 913,212 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 33)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: NTRK2 NM_001007097.3 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0230
• Publications: 0 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: Likely_benign. The variant received -6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BS2: High AC in GnomAdExome4 at 5 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001007097.3. 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.1397-46665A>T		intron	N/A	NP_006171.2
	NTRK2	NM_001007097.3		c.*3796A>T		3_prime_UTR	Exon 15 of 15	NP_001007098.1
	NTRK2	NM_001369539.1		c.*3796A>T		3_prime_UTR	Exon 13 of 13	NP_001356468.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NTRK2	ENST00000359847.4	TSL:1	c.*3796A>T		3_prime_UTR	Exon 14 of 14	ENSP00000352906.3
	NTRK2	ENST00000395882.6	TSL:1	c.*3796A>T		3_prime_UTR	Exon 15 of 15	ENSP00000379221.1
	NTRK2	ENST00000277120.8	TSL:1 MANE Select	c.1397-46665A>T		intron	N/A	ENSP00000277120.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000548 AC: 5 AN: 913212 Hom.: 0 Cov.: 43 AF XY: 0.00000712 AC XY: 3 AN XY: 421550

African (AFR) AF: 0.00 AC: 0 AN: 19634

American (AMR) AF: 0.00 AC: 0 AN: 3442

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 10216

East Asian (EAS) AF: 0.00 AC: 0 AN: 14928

South Asian (SAS) AF: 0.00 AC: 0 AN: 17160

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 334

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2108

European-Non Finnish (NFE) AF: 0.00000616 AC: 5 AN: 811400

Other (OTH) AF: 0.00 AC: 0 AN: 33990

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.67
DANN	Benign	0.72
PhyloP100		-0.023

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: rs1624327; hg19: chr9-87429290;