12-106067532-C-T

Position:

• chr12-106067532-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_014840.3(NUAK1):​c.1256G>A​(p.Gly419Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,884 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 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 nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: NUAK1 NM_014840.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.29

Genes affected

NUAK1 (HGNC:14311): (NUAK family kinase 1) Enables p53 binding activity and protein serine/threonine kinase activity. Involved in several processes, including protein phosphorylation; regulation of cellular senescence; and regulation of myosin-light-chain-phosphatase activity. Located in cytoplasm; microtubule cytoskeleton; and nuclear lumen. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.24796912).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NUAK1	NM_014840.3	c.1256G>A	p.Gly419Asp	missense_variant	7/7	ENST00000261402.7	NP_055655.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NUAK1	ENST00000261402.7	c.1256G>A	p.Gly419Asp	missense_variant	7/7	1	NM_014840.3	ENSP00000261402.2
NUAK1	ENST00000553094.1	c.*47G>A		downstream_gene_variant		4		ENSP00000446873.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461884 Hom.: 0 Cov.: 33 AF XY: 0.00000275 AC XY: 2 AN XY: 727242

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.040	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	19
DANN	Benign	0.96
DEOGEN2	Benign	0.082	T
Eigen	Benign	-0.0056
Eigen_PC	Benign	0.080
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.041	D
MetaRNN	Benign	0.25	T
MetaSVM	Benign	-0.75	T
MutationAssessor	Benign	1.4	L
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-0.39	N
REVEL	Benign	0.15
Sift	Benign	0.078	T
Sift4G	Benign	0.45	T
Polyphen		0.84	P
Vest4		0.36
MutPred		0.27		Gain of catalytic residue at G419 (P = 0.0148);
MVP		0.78
MPC		1.5
ClinPred		0.81	D
GERP RS		5.5
Varity_R		0.16
gMVP		0.31

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

LitVar

Other links and lift over

dbSNP: rs55774704; hg19: chr12-106461310;