chr12-131895067-C-G

Position:

• chr12-131895067-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_003565.4(ULK1):​c.66C>G​(p.Ile22Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 26)
• Consequence: ULK1 NM_003565.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.960

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ULK1	NM_003565.4	c.66C>G	p.Ile22Met	missense_variant	1/28	ENST00000321867.6
ULK1	XM_011538798.4	c.66C>G	p.Ile22Met	missense_variant	1/28
ULK1	XM_011538799.3	c.66C>G	p.Ile22Met	missense_variant	1/28
ULK1	XR_007063134.1	n.446C>G		non_coding_transcript_exon_variant	1/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ULK1	ENST00000321867.6	c.66C>G	p.Ile22Met	missense_variant	1/28	1	NM_003565.4	P1

Frequencies

GnomAD3 genomes Cov.: 26

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 26

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 23, 2024

The c.66C>G (p.I22M) alteration is located in exon 1 (coding exon 1) of the ULK1 gene. This alteration results from a C to G substitution at nucleotide position 66, causing the isoleucine (I) at amino acid position 22 to be replaced by a methionine (M). 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	Pathogenic	0.90
BayesDel_addAF	Benign	-0.036	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.27	T
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.45
FATHMM_MKL	Benign	0.11	N
LIST_S2	Uncertain	0.88	D
M_CAP	Pathogenic	0.61	D
MetaRNN	Uncertain	0.58	D
MetaSVM	Benign	-0.86	T
MutationAssessor	Uncertain	2.6	M
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.94	D
PROVEAN	Benign	-2.0	N
REVEL	Uncertain	0.34
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.50
MutPred		0.77		Gain of disorder (P = 0.0208);
MVP		0.53
MPC		2.3
ClinPred		0.93	D
GERP RS		-5.0
Varity_R		0.63
gMVP		0.75

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-132379612;