17-19776380-G-C

Variant names:

• chr17-19776380-G-C
• rs141459584
• NM_014683.4:c.3080C>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_014683.4(ULK2):​c.3080C>G​(p.Ser1027Trp) variant causes a missense change. The variant allele was found at a frequency of 0.000000689 in 1,452,244 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S1027L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: ULK2 NM_014683.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.82
• Publications: 0 publications found

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.824

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014683.4. 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
	ULK2	NM_014683.4	MANE Select	c.3080C>G	p.Ser1027Trp	missense	Exon 27 of 27	NP_055498.3
	ULK2	NM_001142610.2		c.3080C>G	p.Ser1027Trp	missense	Exon 27 of 28	NP_001136082.1	Q8IYT8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ULK2	ENST00000395544.9	TSL:1 MANE Select	c.3080C>G	p.Ser1027Trp	missense	Exon 27 of 27	ENSP00000378914.4	Q8IYT8
	ULK2	ENST00000361658.6	TSL:1	c.3080C>G	p.Ser1027Trp	missense	Exon 27 of 28	ENSP00000354877.2	Q8IYT8
	ULK2	ENST00000945214.1		c.3095C>G	p.Ser1032Trp	missense	Exon 27 of 27	ENSP00000615273.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.89e-7 AC: 1 AN: 1452244 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 721558

African (AFR) AF: 0.00 AC: 0 AN: 33200

American (AMR) AF: 0.00 AC: 0 AN: 43542

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25728

East Asian (EAS) AF: 0.00 AC: 0 AN: 39356

South Asian (SAS) AF: 0.00 AC: 0 AN: 84178

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52798

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 9.03e-7 AC: 1 AN: 1107700

Other (OTH) AF: 0.00 AC: 0 AN: 59986

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.50	D
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.039	D
MetaRNN	Pathogenic	0.82	D
MetaSVM	Benign	-0.56	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		6.8
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-3.1	D
REVEL	Uncertain	0.35
Sift	Uncertain	0.017	D
Sift4G	Benign	0.15	T
Polyphen		1.0	D
Vest4		0.75
MutPred		0.41		Loss of disorder (P = 0.0165)
MVP		0.85
MPC		0.68
ClinPred		0.98	D
GERP RS		5.8
Varity_R		0.34
gMVP		0.37

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		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: rs141459584; hg19: chr17-19679693;