Genetic Variant ULK2:p.Lys907Glu (chr17-19781025-T-C) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_014683.4(ULK2):c.2719A>G(p.Lys907Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000848 in 1,614,040 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00091 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00084 ( 2 hom. )

Consequence

ULK2
NM_014683.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.56

Variant links:

Genes affected

ULK2 (HGNC:13480): (unc-51 like autophagy activating kinase 2) This gene encodes a protein that is similar to a serine/threonine kinase in C. elegans which is involved in axonal elongation. The structure of this protein is similar to the C. elegans protein in that both proteins have an N-terminal kinase domain, a central proline/serine rich (PS) domain, and a C-terminal (C) domain. The gene is located within the Smith-Magenis syndrome region on chromosome 17. Alternatively spliced transcript variants encoding the same protein have been identified. [provided by RefSeq, Dec 2008]

ULK2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.07677624).

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ULK2	NM_014683.4 link	c.2719A>G	p.Lys907Glu	missense_variant	Exon 24 of 27	ENST00000395544.9	NP_055498.3	Q8IYT8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ULK2	ENST00000395544.9 link	c.2719A>G	p.Lys907Glu	missense_variant	Exon 24 of 27	1	NM_014683.4	ENSP00000378914.4	Q8IYT8
ULK2	ENST00000361658.6 link	c.2719A>G	p.Lys907Glu	missense_variant	Exon 24 of 28	1		ENSP00000354877.2	Q8IYT8
ULK2	ENST00000571454.2 link	n.*61A>G		downstream_gene_variant		5

Frequencies

GnomAD3 genomes

AF:

0.000914

AC:

139

AN:

152104

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000524

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00245

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00137

Gnomad OTH

AF:

0.00192

GnomAD3 exomes

AF:

0.000697

AC:

175

AN:

251076

Hom.:

AF XY:

0.000737

AC XY:

100

AN XY:

135700

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.000318

Gnomad ASJ exome

AF:

0.000199

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00176

Gnomad NFE exome

AF:

0.00104

Gnomad OTH exome

AF:

0.000490

GnomAD4 exome

AF:

0.000841

AC:

1229

AN:

1461818

Hom.:

Cov.:

AF XY:

0.000837

AC XY:

609

AN XY:

727204

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.000313

Gnomad4 ASJ exome

AF:

0.000153

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00191

Gnomad4 NFE exome

AF:

0.000962

Gnomad4 OTH exome

AF:

0.000596

GnomAD4 genome

AF:

0.000913

AC:

139

AN:

152222

Hom.:

Cov.:

AF XY:

0.000927

AC XY:

AN XY:

74432

show subpopulations

Gnomad4 AFR

AF:

0.000168

Gnomad4 AMR

AF:

0.000524

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00245

Gnomad4 NFE

AF:

0.00137

Gnomad4 OTH

AF:

0.00190

Alfa

AF:

0.00110

Hom.:

Bravo

AF:

0.000646

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00105

AC:

ExAC

AF:

0.000626

AC:

EpiCase

AF:

0.000818

EpiControl

AF:

0.000711

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 06, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2719A>G (p.K907E) alteration is located in exon 24 (coding exon 24) of the ULK2 gene. This alteration results from a A to G substitution at nucleotide position 2719, causing the lysine (K) at amino acid position 907 to be replaced by a glutamic acid (E). 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

0.52

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.29

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.27

T;T

Eigen

Uncertain

0.56

Eigen_PC

Uncertain

0.61

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.95

.;D

M_CAP

Benign

0.015

MetaRNN

Benign

0.077

T;T

MetaSVM

Benign

-0.88

MutationAssessor

Uncertain

2.1

M;M

PrimateAI

Uncertain

0.78

PROVEAN

Benign

-2.4

N;N

REVEL

Benign

0.13

Sift

Uncertain

0.026

D;D

Sift4G

Benign

0.10

T;T

Polyphen

0.89

P;P

Vest4

0.63

MVP

0.64

MPC

0.48

ClinPred

0.096

GERP RS

5.6

Varity_R

0.52

gMVP

0.39

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

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