1-88771467-G-C

Variant names:

• chr1-88771467-G-C
• NM_006256.4:c.669G>C

Variant summary

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

The NM_006256.4(PKN2):​c.669G>C​(p.Arg223Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R223K) has been classified 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: 0.565

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKN2	NM_006256.4	c.669G>C	p.Arg223Ser	missense_variant	Exon 5 of 22	ENST00000370521.8	NP_006247.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PKN2	ENST00000370521.8	c.669G>C	p.Arg223Ser	missense_variant	Exon 5 of 22	1	NM_006256.4	ENSP00000359552.3
PKN2	ENST00000370513.9	c.669G>C	p.Arg223Ser	missense_variant	Exon 5 of 21	1		ENSP00000359544.5
PKN2	ENST00000316005.11	c.669G>C	p.Arg223Ser	missense_variant	Exon 5 of 11	5		ENSP00000317851.7
PKN2	ENST00000436111.1	c.12G>C	p.Arg4Ser	missense_variant	Exon 1 of 5	3		ENSP00000401125.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 01, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.669G>C (p.R223S) alteration is located in exon 5 (coding exon 5) of the PKN2 gene. This alteration results from a G to C substitution at nucleotide position 669, causing the arginine (R) at amino acid position 223 to be replaced by a serine (S). 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	Pathogenic	0.78
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.13	T;T;.
Eigen	Benign	-0.039
Eigen_PC	Benign	-0.013
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Pathogenic	0.98	D;D;D
M_CAP	Benign	0.010	T
MetaRNN	Uncertain	0.45	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.3	.;M;M
PrimateAI	Uncertain	0.66	T
PROVEAN	Pathogenic	-5.3	D;D;D
REVEL	Benign	0.22
Sift	Uncertain	0.0040	D;D;D
Sift4G	Uncertain	0.0090	D;T;T
Polyphen		0.10	B;B;.
Vest4		0.53
MutPred		0.73		Loss of catalytic residue at R223 (P = 0.0465);Loss of catalytic residue at R223 (P = 0.0465);Loss of catalytic residue at R223 (P = 0.0465);
MVP		0.50
MPC		0.51
ClinPred		0.96	D
GERP RS		1.4
Varity_R		0.44
gMVP		0.25

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: chr1-89237150;