1-88784760-G-A

Variant summary

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

The NM_006256.4(PKN2):c.1107G>A(p.Met369Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PKN2 NM_006256.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.44

Genes affected

PKN2 (HGNC:9406): (protein kinase N2) Enables RNA polymerase binding activity; histone deacetylase binding activity; and protein serine/threonine kinase activity. Involved in several processes, including apical junction assembly; positive regulation of cell cycle; and positive regulation of viral genome replication. Located in several cellular components, including cleavage furrow; cytoskeleton; and midbody. [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=0.16918236).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PKN2	NM_006256.4	c.1107G>A	p.Met369Ile	missense_variant	7/22	ENST00000370521.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKN2	ENST00000370521.8	c.1107G>A	p.Met369Ile	missense_variant	7/22	1	NM_006256.4	P1
PKN2	ENST00000370513.9	c.1107G>A	p.Met369Ile	missense_variant	7/21	1
PKN2	ENST00000316005.11	c.1107G>A	p.Met369Ile	missense_variant	7/11	5
PKN2	ENST00000436111.1	c.330-1344G>A		intron_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

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

Feb 27, 2024

The c.1107G>A (p.M369I) alteration is located in exon 7 (coding exon 7) of the PKN2 gene. This alteration results from a G to A substitution at nucleotide position 1107, causing the methionine (M) at amino acid position 369 to be replaced by an isoleucine (I). 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	0.29
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
Cadd	Benign	22
Dann	Uncertain	0.98
DEOGEN2	Benign	0.023	T;T;.
Eigen	Benign	-0.064
Eigen_PC	Benign	0.15
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.94	D;D;D
M_CAP	Benign	0.0046	T
MetaRNN	Benign	0.17	T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-1.4	N;N;N
REVEL	Benign	0.063
Sift	Benign	0.29	T;T;T
Sift4G	Benign	0.47	T;T;T
Polyphen		0.0	B;B;.
Vest4		0.27
MutPred		0.14		Gain of glycosylation at S370 (P = 0.0651);Gain of glycosylation at S370 (P = 0.0651);Gain of glycosylation at S370 (P = 0.0651);
MVP		0.28
MPC		0.47
ClinPred		0.62	D
GERP RS		5.6
Varity_R		0.18
gMVP		0.16

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1670502762; hg19: chr1-89250443;