rs185452809

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_007254.4(PNKP):c.1032G>A(p.Arg344Arg) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000756 in 1,593,320 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0039 ( 3 hom., cov: 32)

Exomes 𝑓: 0.00042 ( 2 hom. )

Consequence

PNKP
NM_007254.4 splice_region, synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -1.35

Publications

1 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.62).

BP6

Variant 19-49862279-C-T is Benign according to our data. Variant chr19-49862279-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 138718.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.35 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00395 (601/152292) while in subpopulation AFR AF = 0.0138 (575/41554). AF 95% confidence interval is 0.0129. There are 3 homozygotes in GnomAd4. There are 281 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 3 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.1032G>A	p.Arg344Arg	splice_region synonymous	Exon 12 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.1032G>A	p.Arg344Arg	splice_region synonymous	Exon 12 of 17	ENSP00000323511.2	Q96T60-1
PNKP	ENST00000596014.5	TSL:1	c.1032G>A	p.Arg344Arg	splice_region synonymous	Exon 11 of 16	ENSP00000472300.1	Q96T60-1
PNKP	ENST00000593946.5	TSL:1	n.*959G>A		splice_region non_coding_transcript_exon	Exon 11 of 16	ENSP00000468896.1	M0QX49

Frequencies

GnomAD3 genomes

AF:

0.00387

AC:

589

AN:

152174

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0136

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00124

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00191

GnomAD2 exomes

AF:

0.00108

AC:

227

AN:

209500

AF XY:

0.000802

show subpopulations

Gnomad AFR exome

AF:

0.0158

Gnomad AMR exome

AF:

0.000715

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000109

Gnomad OTH exome

AF:

0.000750

GnomAD4 exome

AF:

0.000418

AC:

603

AN:

1441028

Hom.:

Cov.:

AF XY:

0.000362

AC XY:

259

AN XY:

715016

show subpopulations

African (AFR)

AF:

0.0141

AC:

470

AN:

33296

American (AMR)

AF:

0.000734

AC:

AN:

40854

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25626

East Asian (EAS)

AF:

0.00

AC:

AN:

38906

South Asian (SAS)

AF:

0.0000359

AC:

AN:

83482

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51348

Middle Eastern (MID)

AF:

0.00125

AC:

AN:

5596

European-Non Finnish (NFE)

AF:

0.0000209

AC:

AN:

1102288

Other (OTH)

AF:

0.00117

AC:

AN:

59632

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

115

153

191

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome 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

GnomAD4 genome

AF:

0.00395

AC:

601

AN:

152292

Hom.:

Cov.:

AF XY:

0.00377

AC XY:

281

AN XY:

74472

show subpopulations

African (AFR)

AF:

0.0138

AC:

575

AN:

41554

American (AMR)

AF:

0.00124

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5168

South Asian (SAS)

AF:

0.000621

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68014

Other (OTH)

AF:

0.00189

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

129

161

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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

Alfa

AF:

0.00109

Hom.:

Bravo

AF:

0.00425

Asia WGS

AF:

0.00202

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (3)

not provided (2)

Developmental and epileptic encephalopathy, 12 (1)

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.62

CADD

Benign

2.0

(source)

DANN

Benign

0.75

PhyloP100

-1.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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