1-205303484-C-A

Variant names:

• chr1-205303484-C-A
• rs141288763
• NM_030952.3:c.1853G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_030952.3(NUAK2):​c.1853G>T​(p.Arg618Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000689 in 1,452,268 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign 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. R618Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: NUAK2 NM_030952.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.780
• Publications: 5 publications found

Genes affected

NUAK2 (HGNC:29558): (NUAK family kinase 2) Enables ATP binding activity; magnesium ion binding activity; and protein serine/threonine kinase activity. Involved in several processes, including cellular response to glucose starvation; negative regulation of apoptotic process; and protein phosphorylation. Predicted to be active in cytoplasm. Implicated in anencephaly. [provided by Alliance of Genome Resources, Apr 2022]

NUAK2 Gene-Disease associations (from GenCC):

• anencephaly 2

  Inheritance: AR Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1991531).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_030952.3. 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
	NUAK2	NM_030952.3	MANE Select	c.1853G>T	p.Arg618Leu	missense	Exon 7 of 7	NP_112214.3	Q9H093

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NUAK2	ENST00000367157.6	TSL:1 MANE Select	c.1853G>T	p.Arg618Leu	missense	Exon 7 of 7	ENSP00000356125.5	Q9H093

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000825 AC: 2 AN: 242456 AF XY: 0.00000764

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000111

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.89e-7 AC: 1 AN: 1452268 Hom.: 0 Cov.: 29 AF XY: 0.00000139 AC XY: 1 AN XY: 721970

African (AFR) AF: 0.00 AC: 0 AN: 33172

American (AMR) AF: 0.00 AC: 0 AN: 43608

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25272

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39636

South Asian (SAS) AF: 0.00 AC: 0 AN: 84668

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52916

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5706

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1107326

Other (OTH) AF: 0.00 AC: 0 AN: 59964

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	17
DANN	Uncertain	0.99
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.67
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.084	D
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-0.57	T
PhyloP100		0.78
PrimateAI	Benign	0.26	T
REVEL	Benign	0.080
Sift4G	Uncertain	0.012	D
Vest4		0.44
MVP		0.81
MPC		0.41
ClinPred		0.29	T
GERP RS		2.0
gMVP		0.44
Mutation Taster		=75/25	polymorphism

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

Other links and lift over

dbSNP: rs141288763; hg19: chr1-205272612;