rs752902474

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PP5_Very_Strong

The NM_007254.4(PNKP):c.1386+49_1387-33delCCTCCTCCCCTGACCCC variant causes a intron change involving the alteration of a non-conserved nucleotide. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.00018 ( 0 hom., cov: 0)

Exomes 𝑓: 0.000073 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

PNKP
NM_007254.4 intron

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: 0.0810

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: 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: Likely_pathogenic. The variant received 8 ACMG points.

PP5

Variant 19-49861542-AGGGGTCAGGGGAGGAGG-A is Pathogenic according to our data. Variant chr19-49861542-AGGGGTCAGGGGAGGAGG-A is described in ClinVar as Pathogenic. ClinVar VariationId is 211919.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PNKP	NM_007254.4 link	c.1386+49_1387-33delCCTCCTCCCCTGACCCC		intron_variant	Intron 15 of 16	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.1386+49_1387-33delCCTCCTCCCCTGACCCC		intron_variant	Intron 15 of 16	1	NM_007254.4	ENSP00000323511.2		Q96T60-1

Frequencies

GnomAD3 genomes

AF:

0.000180

AC:

AN:

38794

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000101

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000256

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000619

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000213

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000699

AC:

AN:

171670

AF XY:

0.0000846

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000382

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000787

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000238

Gnomad OTH exome

AF:

0.000246

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000730

AC:

AN:

643952

Hom.:

AF XY:

0.0000782

AC XY:

AN XY:

319620

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

15210

American (AMR)

AF:

0.000396

AC:

AN:

22756

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

9800

East Asian (EAS)

AF:

0.0000879

AC:

AN:

11376

South Asian (SAS)

AF:

0.0000219

AC:

AN:

45722

European-Finnish (FIN)

AF:

0.00

AC:

AN:

22416

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1870

European-Non Finnish (NFE)

AF:

0.0000672

AC:

AN:

491178

Other (OTH)

AF:

0.000127

AC:

AN:

23624

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.606

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

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000180

AC:

AN:

38794

Hom.:

Cov.:

AF XY:

0.000256

AC XY:

AN XY:

19566

show subpopulations

African (AFR)

AF:

0.000101

AC:

AN:

9870

American (AMR)

AF:

0.000256

AC:

AN:

3904

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

1004

East Asian (EAS)

AF:

0.000619

AC:

AN:

1616

South Asian (SAS)

AF:

0.00

AC:

AN:

1242

European-Finnish (FIN)

AF:

0.00

AC:

AN:

1476

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.000213

AC:

AN:

18758

Other (OTH)

AF:

0.00

AC:

AN:

584

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.582

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000540

Hom.:

Bravo

AF:

0.0000604

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Microcephaly, seizures, and developmental delay

Pathogenic:3

Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Mar 01, 2010

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Pathogenic:1

Aug 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PNKP: PM3:Very Strong, PM2, PS3:Supporting -

PNKP-related disorder

Pathogenic:1

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This intron 15 variant has been previously reported as compound heterozygous change in individuals with features of microcephaly, seizures, and developmental delay (MCSZ) (MIM: #613402; PMID: 32980744, 20118933). Experimental studies have shown that this variant disrupts mRNA splicing and causes skipping of exon 15, decreases DNA kinase activity, and results in reduced rates of DNA strand break repair (PMID: 20118933, 22508754). The c.1386+49_1387-33del variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.008% (15/182634) and is absent in the homozygous state; thus it is presumed to be rare. Based on the available evidence, the c.1386+49_1387-33del variant is classified as Pathogenic. -

Developmental and epileptic encephalopathy, 12

Pathogenic:1

May 09, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change falls in intron 15 of the PNKP gene. It does not directly change the encoded amino acid sequence of the PNKP protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs752902474, gnomAD 0.04%). This variant has been observed in individual(s) with PNKP-related microcephaly and seizures (PMID: 20118933). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is also known as g.5646_5662del and exon15fs4X. ClinVar contains an entry for this variant (Variation ID: 211919). Studies have shown that this variant results in skipping of exon 15 and introduces a premature termination codon (PMID: 20118933, 22508754). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.081

Mutation Taster

=2/98

disease causing (ClinVar)

(source)

Splicing

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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over