9-84671000-C-T

Variant names:

• chr9-84671000-C-T
• rs1187326
• NM_006180.6:c.212+40C>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.212+40C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.76 in 1,590,222 control chromosomes in the GnomAD database, including 461,132 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.72 (40402 hom., cov: 32)
  • Exomes 𝑓: 0.76 (420730 hom.)
• Consequence: NTRK2 NM_006180.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.830
• Publications: 20 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 9-84671000-C-T is Benign according to our data. Variant chr9-84671000-C-T is described in ClinVar as Benign. ClinVar VariationId is 1276690.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.765 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NTRK2	NM_006180.6	c.212+40C>T		intron_variant	Intron 2 of 18	ENST00000277120.8	NP_006171.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NTRK2	ENST00000277120.8	c.212+40C>T		intron_variant	Intron 2 of 18	1	NM_006180.6	ENSP00000277120.3

Frequencies

GnomAD3 genomes AF: 0.725 AC: 110163 AN: 151942 Hom.: 40374 Cov.: 32

Gnomad AFR AF: 0.611

Gnomad AMI AF: 0.762

Gnomad AMR AF: 0.745

Gnomad ASJ AF: 0.769

Gnomad EAS AF: 0.757

Gnomad SAS AF: 0.736

Gnomad FIN AF: 0.802

Gnomad MID AF: 0.769

Gnomad NFE AF: 0.771

Gnomad OTH AF: 0.753

GnomAD2 exomes AF: 0.758 AC: 174012 AN: 229630 AF XY: 0.761

Gnomad AFR exome AF: 0.612

Gnomad AMR exome AF: 0.784

Gnomad ASJ exome AF: 0.772

Gnomad EAS exome AF: 0.772

Gnomad FIN exome AF: 0.796

Gnomad NFE exome AF: 0.771

Gnomad OTH exome AF: 0.764

GnomAD4 exome AF: 0.764 AC: 1098708 AN: 1438162 Hom.: 420730 Cov.: 29 AF XY: 0.764 AC XY: 546606 AN XY: 715698

African (AFR) AF: 0.609 AC: 20276 AN: 33296

American (AMR) AF: 0.779 AC: 34370 AN: 44106

Ashkenazi Jewish (ASJ) AF: 0.775 AC: 20175 AN: 26040

East Asian (EAS) AF: 0.737 AC: 29176 AN: 39598

South Asian (SAS) AF: 0.731 AC: 62298 AN: 85226

European-Finnish (FIN) AF: 0.791 AC: 30979 AN: 39168

Middle Eastern (MID) AF: 0.753 AC: 4323 AN: 5738

European-Non Finnish (NFE) AF: 0.771 AC: 851431 AN: 1104976

Other (OTH) AF: 0.761 AC: 45680 AN: 60014

GnomAD4 genome AF: 0.725 AC: 110241 AN: 152060 Hom.: 40402 Cov.: 32 AF XY: 0.727 AC XY: 54014 AN XY: 74302

African (AFR) AF: 0.611 AC: 25351 AN: 41474

American (AMR) AF: 0.745 AC: 11396 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.769 AC: 2670 AN: 3470

East Asian (EAS) AF: 0.757 AC: 3878 AN: 5124

South Asian (SAS) AF: 0.736 AC: 3549 AN: 4822

European-Finnish (FIN) AF: 0.802 AC: 8491 AN: 10582

Middle Eastern (MID) AF: 0.759 AC: 223 AN: 294

European-Non Finnish (NFE) AF: 0.771 AC: 52403 AN: 67978

Other (OTH) AF: 0.750 AC: 1585 AN: 2112

Alfa AF: 0.746 Hom.: 71507

Bravo AF: 0.716

Asia WGS AF: 0.716 AC: 2490 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

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

Obesity, hyperphagia, and developmental delay Benign:1

Sep 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Developmental and epileptic encephalopathy, 58 Benign:1

Sep 05, 2021

Genome-Nilou Lab

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	-0.83
CADD	Benign	1.5
DANN	Benign	0.46
PhyloP100		-0.83
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: rs1187326; hg19: chr9-87285915;