17-19777709-G-C

Position:

• chr17-19777709-G-C

Variant summary

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

The NM_014683.4(ULK2):​c.2924C>G​(p.Ser975Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,455,674 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: ULK2 NM_014683.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.55

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

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	Protein	UniProt
ULK2	NM_014683.4	c.2924C>G	p.Ser975Cys	missense_variant	26/27	ENST00000395544.9	NP_055498.3
ULK2	NM_001142610.2	c.2924C>G	p.Ser975Cys	missense_variant	26/28		NP_001136082.1
ULK2	XM_017025425.3	c.2987C>G	p.Ser996Cys	missense_variant	26/28		XP_016880914.1
ULK2	XM_047437147.1	c.2843C>G	p.Ser948Cys	missense_variant	26/28		XP_047293103.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ULK2	ENST00000395544.9	c.2924C>G	p.Ser975Cys	missense_variant	26/27	1	NM_014683.4	ENSP00000378914.4
ULK2	ENST00000361658.6	c.2924C>G	p.Ser975Cys	missense_variant	26/28	1		ENSP00000354877.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1455674 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 723768

Gnomad4 AFR exome AF: 0.00

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: 9.01e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

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

Jan 03, 2024

The c.2924C>G (p.S975C) alteration is located in exon 26 (coding exon 26) of the ULK2 gene. This alteration results from a C to G substitution at nucleotide position 2924, causing the serine (S) at amino acid position 975 to be replaced by a cysteine (C). 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	Benign	0.10
BayesDel_addAF	Benign	0.0052	T
BayesDel_noAF	Benign	-0.23
CADD	Pathogenic	28
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.49	T;T
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.89	.;D
M_CAP	Benign	0.021	T
MetaRNN	Uncertain	0.55	D;D
MetaSVM	Benign	-0.77	T
MutationAssessor	Benign	1.9	L;L
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-3.4	D;D
REVEL	Uncertain	0.31
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.0020	D;D
Polyphen		0.96	D;D
Vest4		0.58
MutPred		0.39		Loss of disorder (P = 0.0508);Loss of disorder (P = 0.0508);
MVP		0.73
MPC		0.55
ClinPred		0.99	D
GERP RS		5.7
Varity_R		0.58
gMVP		0.51

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: chr17-19681022;