rs752902474

Variant names:

• chr19-49861542-AGGGGTCAGGGGAGGAGG-A
• rs752902474
• NM_007254.4:c.1386+49_1387-33delCCTCCTCCCCTGACCCC

Your query was ambiguous. Multiple possible variants found:

• chr19-49861542-AGGGGTCAGGGGAGGAGG-A
• chr19-49861542-AGGGGTCAGGGGAGGAGG-AGGGGTCAGGGGAGGAGGGGGGTCAGGGGAGGAGG

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PS3 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 (★★). ClinVar reports functional evidence for this variant: "SCV000938474: Studies have shown that this variant results in skipping of exon 15 and introduces a premature termination codon (PMID:20118933, 22508754)." and additional evidence is available in ClinVar.

• 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
• Publications: 2 publications found

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

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000938474: Studies have shown that this variant results in skipping of exon 15 and introduces a premature termination codon (PMID: 20118933, 22508754).; SCV004046229: 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).
• 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.

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.1386+49_1387-33delCCTCCTCCCCTGACCCC		intron	N/A	NP_009185.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PNKP	ENST00000322344.8	TSL:1 MANE Select	c.1386+49_1387-33delCCTCCTCCCCTGACCCC		intron	N/A	ENSP00000323511.2	Q96T60-1
	PNKP	ENST00000596014.5	TSL:1	c.1386+49_1387-33delCCTCCTCCCCTGACCCC		intron	N/A	ENSP00000472300.1	Q96T60-1
	PNKP	ENST00000593946.5	TSL:1	n.*1313+49_*1314-33delCCTCCTCCCCTGACCCC		intron	N/A	ENSP00000468896.1	M0QX49

Frequencies

GnomAD3 genomes AF: 0.000180 AC: 7 AN: 38794 Hom.: 0 Cov.: 0

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: 12 AN: 171670 AF XY: 0.0000846

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

African (AFR) AF: 0.00 AC: 0 AN: 15210

American (AMR) AF: 0.000396 AC: 9 AN: 22756

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 9800

East Asian (EAS) AF: 0.0000879 AC: 1 AN: 11376

South Asian (SAS) AF: 0.0000219 AC: 1 AN: 45722

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 22416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1870

European-Non Finnish (NFE) AF: 0.0000672 AC: 33 AN: 491178

Other (OTH) AF: 0.000127 AC: 3 AN: 23624

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

African (AFR) AF: 0.000101 AC: 1 AN: 9870

American (AMR) AF: 0.000256 AC: 1 AN: 3904

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 1004

East Asian (EAS) AF: 0.000619 AC: 1 AN: 1616

South Asian (SAS) AF: 0.00 AC: 0 AN: 1242

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 1476

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 80

European-Non Finnish (NFE) AF: 0.000213 AC: 4 AN: 18758

Other (OTH) AF: 0.00 AC: 0 AN: 584

Alfa AF: 0.0000540 Hom.: 0

Bravo AF: 0.0000604

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	Microcephaly, seizures, and developmental delay (3)
1	-	-	Developmental and epileptic encephalopathy, 12 (1)
1	-	-	not provided (1)
1	-	-	PNKP-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.081
Mutation Taster		=2/98	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs752902474; hg19: chr19-50364799;