rs3824519

Variant names:

• chr9-84955089-C-T
• rs3824519
• NM_006180.6:c.1938-194C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_006180.6(NTRK2):​c.1938-194C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0903 in 152,224 control chromosomes in the GnomAD database, including 716 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency: Genomes: 𝑓 0.090 (716 hom., cov: 33)
• Consequence: NTRK2 NM_006180.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.79
• Publications: 5 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 9-84955089-C-T is Benign according to our data. Variant chr9-84955089-C-T is described in ClinVar as Benign. ClinVar VariationId is 1269737.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.127 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.1938-194C>T		intron	N/A	NP_006171.2
	NTRK2	NM_001018064.3		c.1890-194C>T		intron	N/A	NP_001018074.1	Q548C2
	NTRK2	NM_001369532.1		c.1890-194C>T		intron	N/A	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.1938-194C>T		intron	N/A	ENSP00000277120.3	Q16620-4
	NTRK2	ENST00000323115.11	TSL:1	c.1854-194C>T		intron	N/A	ENSP00000314586.5	A0A8J8YUT9
	NTRK2	ENST00000686324.1		c.1938-194C>T		intron	N/A	ENSP00000510134.1	Q16620-4

Frequencies

GnomAD3 genomes AF: 0.0902 AC: 13726 AN: 152106 Hom.: 712 Cov.: 33

Gnomad AFR AF: 0.129

Gnomad AMI AF: 0.0932

Gnomad AMR AF: 0.120

Gnomad ASJ AF: 0.0274

Gnomad EAS AF: 0.115

Gnomad SAS AF: 0.0418

Gnomad FIN AF: 0.0512

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.0711

Gnomad OTH AF: 0.0798

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

GnomAD4 genome AF: 0.0903 AC: 13748 AN: 152224 Hom.: 716 Cov.: 33 AF XY: 0.0889 AC XY: 6615 AN XY: 74428

African (AFR) AF: 0.129 AC: 5372 AN: 41514

American (AMR) AF: 0.121 AC: 1843 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0274 AC: 95 AN: 3470

East Asian (EAS) AF: 0.116 AC: 597 AN: 5168

South Asian (SAS) AF: 0.0416 AC: 201 AN: 4826

European-Finnish (FIN) AF: 0.0512 AC: 544 AN: 10618

Middle Eastern (MID) AF: 0.0374 AC: 11 AN: 294

European-Non Finnish (NFE) AF: 0.0711 AC: 4833 AN: 68012

Other (OTH) AF: 0.0789 AC: 167 AN: 2116

Alfa AF: 0.0781 Hom.: 369

Bravo AF: 0.0981

Asia WGS AF: 0.0950 AC: 332 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.21
DANN	Benign	0.54
PhyloP100		-1.8
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: rs3824519; hg19: chr9-87570004;