chr19-49861542-AGGGGTCAGGGGAGGAGG-A

Position:

• chr19-49861542-AGGGGTCAGGGGAGGAGG-A

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PP5_Very_Strong

The NM_007254.4(PNKP):​c.1386+49_1387-33del variant causes a intron change involving the alteration of a non-conserved nucleotide. 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
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 0.0810

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 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 id is 211919.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-49861542-AGGGGTCAGGGGAGGAGG-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PNKP	NM_007254.4	c.1386+49_1387-33del		intron_variant		ENST00000322344.8	NP_009185.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PNKP	ENST00000322344.8	c.1386+49_1387-33del		intron_variant		1	NM_007254.4	ENSP00000323511	P1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 7 AN: 38794 Hom.: 0 Cov.: 0 FAILED QC

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

GnomAD3 exomes AF: 0.0000699 AC: 12 AN: 171670 Hom.: 0 AF XY: 0.0000846 AC XY: 8 AN XY: 94550

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 SAS exome AF: 0.0000516

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: 47 AN: 643952 Hom.: 0 AF XY: 0.0000782 AC XY: 25 AN XY: 319620

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000396

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000879

Gnomad4 SAS exome AF: 0.0000219

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000672

Gnomad4 OTH exome AF: 0.000127

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.000180 AC: 7 AN: 38794 Hom.: 0 Cov.: 0 AF XY: 0.000256 AC XY: 5 AN XY: 19566

Gnomad4 AFR AF: 0.000101

Gnomad4 AMR AF: 0.000256

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000619

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000213

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000540 Hom.: 0

Bravo AF: 0.0000604

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Microcephaly, seizures, and developmental delay Pathogenic:3

Pathogenic, no assertion criteria provided	clinical testing	Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 01, 2010	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Aug 01, 2024

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

PNKP-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

-

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

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 16, 2023

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

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs752902474; hg19: chr19-50364799;