NM_006180.6:c.-69C>G

Variant names:

• chr9-84670680-C-G
• rs1187325
• NM_006180.6:c.-69C>G

Variant summary

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

The NM_006180.6(NTRK2):​c.-69C>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.557 in 1,533,026 control chromosomes in the GnomAD database, including 241,239 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 (20242 hom., cov: 33)
  • Exomes 𝑓: 0.56 (220997 hom.)
• Consequence: NTRK2 NM_006180.6 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.423
• Publications: 12 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=-0.67).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.567 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NTRK2	NM_006180.6	c.-69C>G		5_prime_UTR_variant	Exon 2 of 19	ENST00000277120.8	NP_006171.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NTRK2	ENST00000277120.8	c.-69C>G		5_prime_UTR_variant	Exon 2 of 19	1	NM_006180.6	ENSP00000277120.3

Frequencies

GnomAD3 genomes AF: 0.501 AC: 76229 AN: 152040 Hom.: 20240 Cov.: 33

Gnomad AFR AF: 0.312

Gnomad AMI AF: 0.433

Gnomad AMR AF: 0.566

Gnomad ASJ AF: 0.562

Gnomad EAS AF: 0.584

Gnomad SAS AF: 0.577

Gnomad FIN AF: 0.635

Gnomad MID AF: 0.475

Gnomad NFE AF: 0.567

Gnomad OTH AF: 0.508

GnomAD4 exome AF: 0.563 AC: 777723 AN: 1380870 Hom.: 220997 Cov.: 22 AF XY: 0.563 AC XY: 388945 AN XY: 690728

African (AFR) AF: 0.305 AC: 9734 AN: 31950

American (AMR) AF: 0.648 AC: 28862 AN: 44566

Ashkenazi Jewish (ASJ) AF: 0.562 AC: 14402 AN: 25638

East Asian (EAS) AF: 0.584 AC: 22969 AN: 39342

South Asian (SAS) AF: 0.569 AC: 48017 AN: 84452

European-Finnish (FIN) AF: 0.626 AC: 27987 AN: 44730

Middle Eastern (MID) AF: 0.482 AC: 1951 AN: 4044

European-Non Finnish (NFE) AF: 0.565 AC: 591994 AN: 1048296

Other (OTH) AF: 0.550 AC: 31807 AN: 57852

GnomAD4 genome AF: 0.501 AC: 76245 AN: 152156 Hom.: 20242 Cov.: 33 AF XY: 0.506 AC XY: 37653 AN XY: 74416

African (AFR) AF: 0.312 AC: 12939 AN: 41528

American (AMR) AF: 0.567 AC: 8673 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.562 AC: 1949 AN: 3470

East Asian (EAS) AF: 0.584 AC: 3001 AN: 5138

South Asian (SAS) AF: 0.579 AC: 2791 AN: 4824

European-Finnish (FIN) AF: 0.635 AC: 6732 AN: 10604

Middle Eastern (MID) AF: 0.452 AC: 133 AN: 294

European-Non Finnish (NFE) AF: 0.567 AC: 38571 AN: 67974

Other (OTH) AF: 0.503 AC: 1062 AN: 2112

Alfa AF: 0.404 Hom.: 1192

Bravo AF: 0.485

Asia WGS AF: 0.505 AC: 1758 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	7.4
DANN	Benign	0.82
PhyloP100		-0.42
PromoterAI		0.027	Neutral
Mutation Taster		=300/0	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: rs1187325; hg19: chr9-87285595; COSMIC: COSV52861221;