1-88741007-C-G

Variant names:

• chr1-88741007-C-G
• rs375306359
• NM_006256.4:c.68C>G

Variant summary

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

The NM_006256.4(PKN2):​c.68C>G​(p.Pro23Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000706 in 1,415,998 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 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. P23L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: PKN2 NM_006256.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.10
• Publications: 0 publications found

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

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=0.118790746).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006256.4. 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
	PKN2	NM_006256.4	MANE Select	c.68C>G	p.Pro23Arg	missense	Exon 2 of 22	NP_006247.1	Q16513-1
	PKN2	NM_001320709.2		c.68C>G	p.Pro23Arg	missense	Exon 2 of 22	NP_001307638.1	Q16513-2
	PKN2	NM_001320707.2		c.68C>G	p.Pro23Arg	missense	Exon 2 of 21	NP_001307636.1	Q16513-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKN2	ENST00000370521.8	TSL:1 MANE Select	c.68C>G	p.Pro23Arg	missense	Exon 2 of 22	ENSP00000359552.3	Q16513-1
	PKN2	ENST00000370513.9	TSL:1	c.68C>G	p.Pro23Arg	missense	Exon 2 of 21	ENSP00000359544.5	Q16513-3
	PKN2	ENST00000866345.1		c.110C>G	p.Pro37Arg	missense	Exon 3 of 23	ENSP00000536404.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.06e-7 AC: 1 AN: 1415998 Hom.: 0 Cov.: 30 AF XY: 0.00000142 AC XY: 1 AN XY: 702366

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 30834

American (AMR) AF: 0.00 AC: 0 AN: 32864

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23696

East Asian (EAS) AF: 0.00 AC: 0 AN: 39048

South Asian (SAS) AF: 0.00 AC: 0 AN: 78054

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52166

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5540

European-Non Finnish (NFE) AF: 9.13e-7 AC: 1 AN: 1095470

Other (OTH) AF: 0.00 AC: 0 AN: 58326

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.097	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	20
DANN	Benign	0.94
DEOGEN2	Benign	0.026	T
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.22
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.025	D
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.69	N
PhyloP100		2.1
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.011
Sift	Benign	0.059	T
Sift4G	Benign	0.51	T
Polyphen		0.39	B
Vest4		0.32
MutPred		0.29		Gain of methylation at P23 (P = 0.0258)
MVP		0.42
MPC		0.46
ClinPred		0.19	T
GERP RS		1.0
Varity_R		0.041
gMVP		0.22
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs375306359; hg19: chr1-89206690;