rs3739186

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_007254.4(PNKP):c.586T>A(p.Tyr196Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00185 in 1,614,084 control chromosomes in the GnomAD database, including 46 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y196C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0098 ( 25 hom., cov: 33)

Exomes 𝑓: 0.0010 ( 21 hom. )

Consequence

PNKP
NM_007254.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 7.52

Publications

9 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: Laboratory for Molecular Medicine, G2P, Orphanet
microcephaly, seizures, and developmental delay
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen
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: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008716047).

BP6

Variant 19-49864229-A-T is Benign according to our data. Variant chr19-49864229-A-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 138709.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00985 (1499/152234) while in subpopulation AFR AF = 0.0337 (1399/41534). AF 95% confidence interval is 0.0322. There are 25 homozygotes in GnomAd4. There are 711 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 25 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_007254.4. 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
	PNKP	NM_007254.4	MANE Select	c.586T>A	p.Tyr196Asn	missense	Exon 6 of 17	NP_009185.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PNKP	ENST00000322344.8	TSL:1 MANE Select	c.586T>A	p.Tyr196Asn	missense	Exon 6 of 17	ENSP00000323511.2	Q96T60-1
PNKP	ENST00000596014.5	TSL:1	c.586T>A	p.Tyr196Asn	missense	Exon 5 of 16	ENSP00000472300.1	Q96T60-1
PNKP	ENST00000593946.5	TSL:1	n.*513T>A		non_coding_transcript_exon	Exon 5 of 16	ENSP00000468896.1	M0QX49

Frequencies

GnomAD3 genomes

AF:

0.00983

AC:

1496

AN:

152116

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0337

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00471

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000206

Gnomad OTH

AF:

0.00670

GnomAD2 exomes

AF:

0.00261

AC:

657

AN:

251434

AF XY:

0.00187

show subpopulations

Gnomad AFR exome

AF:

0.0339

Gnomad AMR exome

AF:

0.00197

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000193

Gnomad OTH exome

AF:

0.00195

GnomAD4 exome

AF:

0.00101

AC:

1481

AN:

1461850

Hom.:

Cov.:

AF XY:

0.000835

AC XY:

607

AN XY:

727234

show subpopulations

African (AFR)

AF:

0.0332

AC:

1110

AN:

33478

American (AMR)

AF:

0.00208

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.000174

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53404

Middle Eastern (MID)

AF:

0.00260

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000701

AC:

AN:

1111988

Other (OTH)

AF:

0.00281

AC:

170

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

101

202

302

403

504

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

114

152

190

<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

AF:

0.00985

AC:

1499

AN:

152234

Hom.:

Cov.:

AF XY:

0.00955

AC XY:

711

AN XY:

74452

show subpopulations

African (AFR)

AF:

0.0337

AC:

1399

AN:

41534

American (AMR)

AF:

0.00471

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5170

South Asian (SAS)

AF:

0.00

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000206

AC:

AN:

68014

Other (OTH)

AF:

0.00664

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

134

202

269

336

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00281

Hom.:

Bravo

AF:

0.0111

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.0379

AC:

167

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.00324

AC:

393

Asia WGS

AF:

0.00231

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.000296

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

not specified (2)

Developmental and epileptic encephalopathy, 12 (1)

Inborn genetic diseases (1)

Microcephaly, seizures, and developmental delay (1)

PNKP-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.46

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.24

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.12

Eigen

Uncertain

0.45

Eigen_PC

Uncertain

0.47

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.97

MetaRNN

Benign

0.0087

MetaSVM

Benign

-0.72

MutationAssessor

Benign

1.4

PhyloP100

7.5

PrimateAI

Uncertain

0.58

PROVEAN

Pathogenic

-6.7

REVEL

Benign

0.23

Sift

Pathogenic

0.0

Sift4G

Benign

0.21

Polyphen

1.0

Vest4

0.79

MVP

0.86

MPC

0.28

ClinPred

0.065

GERP RS

5.6

Varity_R

0.79

gMVP

0.76

Mutation Taster

=95/5

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over