rs56142442

Variant names:

• chr9-85021350-C-T
• rs56142442
• NM_006180.6:c.2430C>T

Your query was ambiguous. Multiple possible variants found:

• chr9-85021350-C-T
• chr9-85021350-C-A
• chr9-85021350-C-G

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_006180.6(NTRK2):​c.2430C>T​(p.Pro810Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00171 in 1,614,132 control chromosomes in the GnomAD database, including 96 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0023 (9 hom., cov: 32)
  • Exomes 𝑓: 0.0016 (87 hom.)
• Consequence: NTRK2 NM_006180.6 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.0980
• Publications: 9 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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.42).
• BP6: Variant 9-85021350-C-T is Benign according to our data. Variant chr9-85021350-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 285975.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00231 (352/152250) while in subpopulation AMR AF = 0.0193 (296/15300). AF 95% confidence interval is 0.0175. There are 9 homozygotes in GnomAd4. There are 182 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 352 AD gene.

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.2430C>T	p.Pro810Pro	synonymous	Exon 19 of 19	NP_006171.2
	NTRK2	NM_001018064.3		c.2382C>T	p.Pro794Pro	synonymous	Exon 18 of 18	NP_001018074.1	Q548C2
	NTRK2	NM_001369532.1		c.2382C>T	p.Pro794Pro	synonymous	Exon 19 of 19	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.2430C>T	p.Pro810Pro	synonymous	Exon 19 of 19	ENSP00000277120.3	Q16620-4
	NTRK2	ENST00000323115.11	TSL:1	c.2346C>T	p.Pro782Pro	synonymous	Exon 17 of 17	ENSP00000314586.5	A0A8J8YUT9
	NTRK2	ENST00000686324.1		c.2430C>T	p.Pro810Pro	synonymous	Exon 19 of 19	ENSP00000510134.1	Q16620-4

Frequencies

GnomAD3 genomes AF: 0.00231 AC: 351 AN: 152134 Hom.: 9 Cov.: 32

Gnomad AFR AF: 0.000869

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0193

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00574

GnomAD2 exomes AF: 0.00738 AC: 1855 AN: 251304 AF XY: 0.00554

Gnomad AFR exome AF: 0.00105

Gnomad AMR exome AF: 0.0516

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000123

Gnomad OTH exome AF: 0.00587

GnomAD4 exome AF: 0.00165 AC: 2412 AN: 1461882 Hom.: 87 Cov.: 31 AF XY: 0.00141 AC XY: 1029 AN XY: 727242

African (AFR) AF: 0.000508 AC: 17 AN: 33480

American (AMR) AF: 0.0500 AC: 2236 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000104 AC: 9 AN: 86258

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53420

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.0000567 AC: 63 AN: 1112000

Other (OTH) AF: 0.00141 AC: 85 AN: 60396

GnomAD4 genome AF: 0.00231 AC: 352 AN: 152250 Hom.: 9 Cov.: 32 AF XY: 0.00245 AC XY: 182 AN XY: 74432

African (AFR) AF: 0.000866 AC: 36 AN: 41548

American (AMR) AF: 0.0193 AC: 296 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 68004

Other (OTH) AF: 0.00568 AC: 12 AN: 2112

Alfa AF: 0.00113 Hom.: 1

Bravo AF: 0.00485

Asia WGS AF: 0.00173 AC: 6 AN: 3476

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	-	1	not provided (1)
-	-	1	Obesity, hyperphagia, and developmental delay;C4693367:Developmental and epileptic encephalopathy, 58 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.42
CADD	Benign	5.5
DANN	Benign	0.67
PhyloP100		-0.098
Mutation Taster		=92/8	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: rs56142442; hg19: chr9-87636265;