chr12-106067007-G-T

Position:

• chr12-106067007-G-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.1781C>A​(p.Ala594Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,870 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: NUAK1 NM_014840.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.56

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=0.1049498).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NUAK1	NM_014840.3	c.1781C>A	p.Ala594Asp	missense_variant	7/7	ENST00000261402.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NUAK1	ENST00000261402.7	c.1781C>A	p.Ala594Asp	missense_variant	7/7	1	NM_014840.3	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461870 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 727232

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: 0.00000629

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

Apr 12, 2022

The c.1781C>A (p.A594D) alteration is located in exon 7 (coding exon 7) of the NUAK1 gene. This alteration results from a C to A substitution at nucleotide position 1781, causing the alanine (A) at amino acid position 594 to be replaced by an aspartic acid (D). 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	0.13
BayesDel_addAF	Benign	-0.094	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	16
DANN	Uncertain	0.98
DEOGEN2	Benign	0.032	T
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.21
FATHMM_MKL	Benign	0.76	D
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.10	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.5	L
MutationTaster	Benign	0.98	N
PrimateAI	Benign	0.35	T
PROVEAN	Benign	0.15	N
REVEL	Benign	0.038
Sift	Benign	0.069	T
Sift4G	Benign	0.60	T
Polyphen		0.26	B
Vest4		0.11
MutPred		0.27		Gain of relative solvent accessibility (P = 0.0249);
MVP		0.74
MPC		0.69
ClinPred		0.16	T
GERP RS		3.1
Varity_R		0.11
gMVP		0.56

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: chr12-106460785;