dbSNP rs950502049: PNKP:p.Arg431Pro (chr19-49861778-C-G) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_007254.4(PNKP):c.1292G>C(p.Arg431Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000142 in 1,410,282 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. R431C) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

PNKP
NM_007254.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.14

Publications

0 publications found

Variant links:

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, SUPPORTIVE Submitted by: Orphanet, G2P, Laboratory for Molecular Medicine
microcephaly, seizures, and developmental delay
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae)
Charcot-Marie-Tooth disease type 2B2
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
genetic developmental and epileptic encephalopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

PNKP links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.901

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PNKP	NM_007254.4 link	c.1292G>C	p.Arg431Pro	missense_variant	Exon 14 of 17	ENST00000322344.8	NP_009185.2	Q96T60-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PNKP	ENST00000322344.8 link	c.1292G>C	p.Arg431Pro	missense_variant	Exon 14 of 17	1	NM_007254.4	ENSP00000323511.2		Q96T60-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000142

AC:

AN:

1410282

Hom.:

Cov.:

AF XY:

0.00000143

AC XY:

AN XY:

697604

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31780

American (AMR)

AF:

0.00

AC:

AN:

36602

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25490

East Asian (EAS)

AF:

0.00

AC:

AN:

35958

South Asian (SAS)

AF:

0.00

AC:

AN:

80604

European-Finnish (FIN)

AF:

0.00

AC:

AN:

47354

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5714

European-Non Finnish (NFE)

AF:

0.00000184

AC:

AN:

1088224

Other (OTH)

AF:

0.00

AC:

AN:

58556

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Uncertain

0.16

BayesDel_noAF

Uncertain

-0.010

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.69

D;D;D;T

Eigen

Uncertain

0.44

Eigen_PC

Uncertain

0.22

FATHMM_MKL

Benign

0.56

LIST_S2

Uncertain

0.92

.;D;D;D

M_CAP

Pathogenic

0.62

MetaRNN

Pathogenic

0.90

D;D;D;D

MetaSVM

Uncertain

0.091

MutationAssessor

Pathogenic

3.6

H;.;H;.

PhyloP100

1.1

PrimateAI

Uncertain

0.57

PROVEAN

Pathogenic

-6.6

D;.;.;.

REVEL

Uncertain

0.33

Sift

Pathogenic

0.0

D;.;.;.

Sift4G

Pathogenic

0.0

D;D;D;D

Polyphen

1.0

D;.;D;.

Vest4

0.75

MutPred

0.64

Gain of helix (P = 0.0078);.;Gain of helix (P = 0.0078);.;

MVP

0.80

MPC

0.57

ClinPred

0.97

GERP RS

3.9

PromoterAI

-0.049

Neutral

(source)

Varity_R

0.98

gMVP

0.97

Mutation Taster

=43/57

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over