Variant 10-62217189-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_145307.4(RTKN2):c.949C>T(p.Leu317Phe) variant causes a missense change. The variant allele was found at a frequency of 0.0000725 in 1,599,806 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000054 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000074 ( 0 hom. )

Consequence

RTKN2
NM_145307.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.57

Variant links:

Genes affected

RTKN2 (HGNC:19364): (rhotekin 2) Involved in negative regulation of intrinsic apoptotic signaling pathway; positive regulation of NF-kappaB transcription factor activity; and positive regulation of NIK/NF-kappaB signaling. Located in cytoplasm and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

RTKN2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.795

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RTKN2	NM_145307.4 linkuse as main transcript	c.949C>T	p.Leu317Phe	missense_variant	9/12	ENST00000373789.8	NP_660350.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RTKN2	ENST00000373789.8 linkuse as main transcript	c.949C>T	p.Leu317Phe	missense_variant	9/12	1	NM_145307.4	ENSP00000362894	P1	Q8IZC4-1
RTKN2	ENST00000315289.6 linkuse as main transcript	c.292C>T	p.Leu98Phe	missense_variant	4/9	2		ENSP00000325379

Frequencies

GnomAD3 genomes

AF:

0.0000536

AC:

AN:

149270

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000670

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000212

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000888

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000205

AC:

AN:

243626

Hom.:

AF XY:

0.0000303

AC XY:

AN XY:

131974

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000450

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000745

AC:

108

AN:

1450448

Hom.:

Cov.:

AF XY:

0.0000721

AC XY:

AN XY:

721440

show subpopulations

Gnomad4 AFR exome

AF:

0.0000304

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000931

Gnomad4 OTH exome

AF:

0.0000668

GnomAD4 genome

AF:

0.0000536

AC:

AN:

149358

Hom.:

Cov.:

AF XY:

0.0000551

AC XY:

AN XY:

72596

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000669

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000212

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000888

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000108

Hom.:

Bravo

AF:

0.0000567

ExAC

AF:

0.0000330

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 24, 2023

The c.949C>T (p.L317F) alteration is located in exon 9 (coding exon 9) of the RTKN2 gene. This alteration results from a C to T substitution at nucleotide position 949, causing the leucine (L) at amino acid position 317 to be replaced by a phenylalanine (F). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.38

BayesDel_addAF

Pathogenic

0.45

BayesDel_noAF

Pathogenic

0.41

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.69

.;D

Eigen

Pathogenic

0.84

Eigen_PC

Pathogenic

0.84

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.84

T;T

M_CAP

Benign

0.038

MetaRNN

Pathogenic

0.79

D;D

MetaSVM

Pathogenic

0.85

MutationAssessor

Uncertain

2.5

.;M

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.54

PROVEAN

Uncertain

-3.6

D;D

REVEL

Pathogenic

0.67

Sift

Uncertain

0.0060

D;D

Sift4G

Uncertain

0.0070

D;D

Polyphen

1.0

D;D

Vest4

0.86

MVP

0.81

MPC

0.29

ClinPred

0.95

GERP RS

6.2

Varity_R

0.58

gMVP

0.77

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over