rs587784366

Variant names:

• chr19-49861765-ACGCTACCTGG-A
• rs587784366
• NM_007254.4:c.1295_1298+6delCCAGGTAGCG

Your query was ambiguous. Multiple possible variants found:

• chr19-49861765-ACGCTACCTGG-A
• chr19-49861765-ACGCTACCTGG-ACGCTACCTGGCGCTACCTGG

Variant summary

Our verdict is Pathogenic. The variant received 20 ACMG points: 20P and 0B. PVS1 PS3 PP5_Very_Strong

The NM_007254.4(PNKP):​c.1295_1298+6delCCAGGTAGCG​(p.Ala432fs) variant causes a frameshift, splice donor, splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000046 in 1,566,646 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000966857: Functional studies in patient fibroblasts provide some evidence that this variant reduced protein expression and activity and were more susceptible to single strand breaks due to reduced repair activity (Kalasova 2019 PMID:31041400, Kalasova 2020 PMID:32504494).; SCV001236133: Experimental studies have shown that this variant affects PNKP function (PMID:32504494).; SCV005205240: At least one publication reports experimental evidence evaluating an impact on protein function, and demonstrated strongly reduced protein level and reduced function in patient derived cells (Kalasova_2020). PMID:32504494". Synonymous variant affecting the same amino acid position (i.e. A432A) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000047 (0 hom.)
• Consequence: PNKP NM_007254.4 frameshift, splice_donor, splice_region, intron
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 3.56
• 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 20 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV000966857: Functional studies in patient fibroblasts provide some evidence that this variant reduced protein expression and activity and were more susceptible to single strand breaks due to reduced repair activity (Kalasova 2019 PMID: 31041400, Kalasova 2020 PMID: 32504494).; SCV001236133: Experimental studies have shown that this variant affects PNKP function (PMID: 32504494).; SCV005205240: At least one publication reports experimental evidence evaluating an impact on protein function, and demonstrated strongly reduced protein level and reduced function in patient derived cells (Kalasova_2020). PMID: 32504494
• PP5: Variant 19-49861765-ACGCTACCTGG-A is Pathogenic according to our data. Variant chr19-49861765-ACGCTACCTGG-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 159788.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.1295_1298+6delCCAGGTAGCG	p.Ala432fs	frameshift splice_donor splice_region intron	Exon 14 of 17	NP_009185.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PNKP	ENST00000322344.8	TSL:1 MANE Select	c.1295_1298+6delCCAGGTAGCG	p.Ala432fs	frameshift splice_donor splice_region intron	Exon 14 of 17	ENSP00000323511.2	Q96T60-1
	PNKP	ENST00000596014.5	TSL:1	c.1295_1298+6delCCAGGTAGCG	p.Ala432fs	frameshift splice_donor splice_region intron	Exon 13 of 16	ENSP00000472300.1	Q96T60-1
	PNKP	ENST00000593946.5	TSL:1	n.*1222_*1225+6delCCAGGTAGCG		splice_region non_coding_transcript_exon	Exon 13 of 16	ENSP00000468896.1	M0QX49

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152120 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000683 AC: 12 AN: 175710 AF XY: 0.0000848

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000685

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000474 AC: 67 AN: 1414526 Hom.: 0 AF XY: 0.0000586 AC XY: 41 AN XY: 699848

African (AFR) AF: 0.00 AC: 0 AN: 32080

American (AMR) AF: 0.00 AC: 0 AN: 37672

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25454

East Asian (EAS) AF: 0.00 AC: 0 AN: 36650

South Asian (SAS) AF: 0.000296 AC: 24 AN: 80952

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48930

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5696

European-Non Finnish (NFE) AF: 0.0000349 AC: 38 AN: 1088520

Other (OTH) AF: 0.0000854 AC: 5 AN: 58572

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152120 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74298

African (AFR) AF: 0.00 AC: 0 AN: 41406

American (AMR) AF: 0.00 AC: 0 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68006

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.0000227

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	not provided (3)
2	-	-	Microcephaly, seizures, and developmental delay (2)
1	-	-	Ataxia, early-onset, with oculomotor apraxia and hypoalbuminemia (1)
1	-	-	Developmental and epileptic encephalopathy, 12 (1)
1	-	-	PNKP-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.6
Mutation Taster		=1/199	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs587784366; hg19: chr19-50365022;