NM_007254.4:c.853A>G

Variant names:

• chr19-49862702-T-C
• rs750224965
• NM_007254.4:c.853A>G
• PNKP p.Ile285Val

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

0 Uncertain · Cold

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 0 classification points (ACMG Germline Pathogenicity v2019). PM2BP4_Moderate

The NM_007254.4(PNKP):c.853A>G (p.Ile285Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.0000124 (AC=20) in the gnomAD database across 1,613,962 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.0000081. In-silico predictor (REVEL) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain Significance (★★). Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.I285F: Uncertain_significance (ClinVar VariationId 1363093, 1 star); p.I285M: Uncertain_significance (ClinVar VariationId 1763848, 1 star)

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: PNKP NM_007254.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: -2.03
• Publications: 0 publications found

Genes affected

PNKP (HGNC:9154): (polynucleotide kinase 3'-phosphatase) This locus represents a gene involved in DNA repair. In response to ionizing radiation or oxidative damage, the protein encoded by this locus catalyzes 5' phosphorylation and 3' dephosphorylation of nucleic acids. Mutations at this locus have been associated with microcephaly, seizures, and developmental delay.[provided by RefSeq, Sep 2010]

PNKP Gene-Disease associations (from GenCC):

• ataxia - oculomotor apraxia type 4

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Laboratory for Molecular Medicine, Orphanet, G2P, PanelApp Australia
• microcephaly, seizures, and developmental delay

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen
• Charcot-Marie-Tooth disease type 2B2

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: PanelApp Australia, Orphanet, Labcorp Genetics (formerly Invitae)
• genetic developmental and epileptic encephalopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Uncertain_significance. The variant received 0 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM2Absent/extremely low in population databases		Very rare in gnomAD for AD/XL gene (popmax AF < threshold/10) — PM2; GnomAD popmax AF = 0.0000081 — very rare for AD+AR gene (base 0.0001, raised to 0.0005 by highest known P/LP ClinVar AF 0.00178) — PM2 moderate.
	BP4Computational evidence suggests no impact		Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Moderate).

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_007254.4. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	PNKP NM_007254.4	MANE Select	c.853A>G p.Ile285Val	missense	Exon 9 of 17	Prot: NP_009185.2

PNKP NM_007254.4

MANE Select

HGVSc / HGVSpc.853A>Gp.Ile285Val

Exon rankExon 9 of 17

missense

Prot: NP_009185.2

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	PNKP ENST00000322344.8	TSL:1MANE Select	c.853A>G p.Ile285Val	missense	Exon 9 of 17	Prot: ENSP00000323511.2 UniProt:
	PNKP ENST00000596014.5	TSL:1	c.853A>G p.Ile285Val	missense	Exon 8 of 16	Prot: ENSP00000472300.1 UniProt:
	PNKP ENST00000593946.5	TSL:1	n.*780A>G	3_prime_UTR	Exon 8 of 16	Prot: ENSP00000468896.1 UniProt:

PNKP ENST00000322344.8

TSL:1MANE Select

HGVSc / HGVSpc.853A>Gp.Ile285Val

Exon rankExon 9 of 17

missense

Prot: ENSP00000323511.2UniProt: Q96T60-1

PNKP ENST00000596014.5

TSL:1

HGVSc / HGVSpc.853A>Gp.Ile285Val

Exon rankExon 8 of 16

missense

Prot: ENSP00000472300.1UniProt: Q96T60-1

PNKP ENST00000593946.5

TSL:1

HGVSc / HGVSpn.*780A>G

Exon rankExon 8 of 16

3_prime_UTR

Prot: ENSP00000468896.1UniProt: M0QX49

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 6 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.00000657	AC:1	Hom:0	AN:152134	Cov:33
GnomAD2 exomes	AF: 0.0000119	AC:3	Hom:	AN:251292	Cov:
GnomAD4 exome	AF: 0.0000130	AC:19	Hom:0	AN:1461828	Cov:35
GnomAD4 genome	AF: 0.00000657	AC:1	Hom:0	AN:152134	Cov:33
TOPMed (Bravo)	AF: 0.0000340	AC:9	Hom:0	AN:264690	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.00	AC:0	Hom:0	AN:16840	Cov:

Showing 6 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
BipEx(Bipolar disorder (including schizoaffective))	0.0000352	1	28420	0.00	0	28844
SCHEMA(Schizophrenia)	0.0000586	3	51158	0.0000545	5	91790

Showing 2 cohortsAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	not provided (2)
-	1	-	Developmental and epileptic encephalopathy, 12 (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Benign	0.56
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	0.063
DANN	Benign	0.57
DEOGEN2	Benign	0.051	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.0053	N
FuncVEP CTI	Benign	0.0031
GPN-Star LLR	N/A	-0.55
GPN-Star score	N/A	0.55
LIST_S2	Benign	0.72	T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.10	T
MetaSVM	Benign	-1.1	T
Mutation Taster	N/A	97/3	polymorphism
MutationAssessor	Benign	0.065	N
PhyloP100	Benign	-2.0
popEVE	Benign	-2.4
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.69	N
RBP_binding_hub_radar	N/A	0.0
RBP_regulation_power_radar	N/A	1.1
REVEL	Benign	0.18
Sift	Benign	0.83	T
Sift4G	Benign	0.63	T
Varity_R	N/A	0.019
VESM-3B	Benign	-4.1

Showing 30 of 30 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.0
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs750224965;

hg19: chr19-50365959;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar