Genetic Variant ULK1:p.Arg18Cys (chr12-131895053-C-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_003565.4(ULK1):c.52C>T(p.Arg18Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000349 in 1,434,262 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 26)

Exomes 𝑓: 0.0000035 ( 0 hom. )

Consequence

ULK1
NM_003565.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.749

Publications

1 publications found

Variant links:

Genes affected

ULK1 (HGNC:12558): (unc-51 like autophagy activating kinase 1) Enables identical protein binding activity; protein serine/threonine kinase activity; and small GTPase binding activity. Involved in several processes, including autophagosome assembly; positive regulation by symbiont of host autophagy; and protein phosphorylation. Located in autophagosome; cytosol; and phagophore assembly site membrane. Is extrinsic component of autophagosome membrane; extrinsic component of omegasome membrane; and extrinsic component of phagophore assembly site membrane. Part of Atg1/ULK1 kinase complex. [provided by Alliance of Genome Resources, Apr 2022]

ULK1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003565.4. 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
	ULK1	NM_003565.4	MANE Select	c.52C>T	p.Arg18Cys	missense	Exon 1 of 28	NP_003556.2	O75385

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ULK1	ENST00000321867.6	TSL:1 MANE Select	c.52C>T	p.Arg18Cys	missense	Exon 1 of 28	ENSP00000324560.3	O75385
ULK1	ENST00000939866.1		c.52C>T	p.Arg18Cys	missense	Exon 1 of 28	ENSP00000609925.1
ULK1	ENST00000939867.1		c.52C>T	p.Arg18Cys	missense	Exon 1 of 28	ENSP00000609926.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000990

AC:

AN:

202022

AF XY:

0.00000890

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000319

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000110

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000349

AC:

AN:

1434262

Hom.:

Cov.:

AF XY:

0.00000561

AC XY:

AN XY:

712980

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32476

American (AMR)

AF:

0.0000236

AC:

AN:

42412

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25564

East Asian (EAS)

AF:

0.00

AC:

AN:

37798

South Asian (SAS)

AF:

0.00

AC:

AN:

83506

European-Finnish (FIN)

AF:

0.00

AC:

AN:

42264

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5706

European-Non Finnish (NFE)

AF:

0.00000271

AC:

AN:

1105082

Other (OTH)

AF:

0.0000168

AC:

AN:

59454

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000853

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.81

BayesDel_addAF

Benign

-0.088

BayesDel_noAF

Benign

-0.36

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.36

Eigen

Benign

0.095

Eigen_PC

Benign

-0.0052

FATHMM_MKL

Benign

0.59

LIST_S2

Uncertain

0.95

M_CAP

Pathogenic

0.86

MetaRNN

Uncertain

0.51

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.4

PhyloP100

0.75

PrimateAI

Pathogenic

0.97

PROVEAN

Uncertain

-3.5

REVEL

Benign

0.21

Sift

Uncertain

0.0040

Sift4G

Uncertain

0.0090

Polyphen

0.99

Vest4

0.40

MutPred

0.58

Gain of methylation at K19 (P = 0.0224)

MVP

0.20

MPC

2.3

ClinPred

0.89

GERP RS

0.82

PromoterAI

0.030

Neutral

(source)

Varity_R

0.67

gMVP

0.88

Mutation Taster

=38/62

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over