rs199919568

Variant names:

• chr19-49862369-A-G
• rs199919568
• NM_007254.4:c.1029+2T>C

Your query was ambiguous. Multiple possible variants found:

• chr19-49862369-A-G
• chr19-49862369-A-C

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PVS1_Moderate PS3 PP5

The NM_007254.4(PNKP):​c.1029+2T>C variant causes a splice donor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00178 in 1,280,492 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). ClinVar reports functional evidence for this variant: "SCV000242059: RNA studies and functional RNA analyses demonstrate a damaging effect and indicate aberrant splicing in response to c.1029+2T>C resulting predominately in skipping of exon 11, affecting the phosphatase domain and the kinase domain (PMID:37301908, 34697416, 22508754)" and additional evidence is available in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0019 (0 hom.)
• Consequence: PNKP NM_007254.4 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:26 U:3
• Conservation: PhyloP100: 3.19
• Publications: 12 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: Likely_pathogenic. The variant received 7 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.059386972 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV000242059: RNA studies and functional RNA analyses demonstrate a damaging effect and indicate aberrant splicing in response to c.1029+2T>C resulting predominately in skipping of exon 11, affecting the phosphatase domain and the kinase domain (PMID: 37301908, 34697416, 22508754); SCV003922343: RNAseq showed exon 11 skipping, which is in-frame and is predicted to escape nonsense mediated decay (NMD) (Neuser 2021 PMID: 34697416; Wai 2020 PMID: 32123317).; SCV000650110: Studies have shown that disruption of this splice site results in skipping of exon 11 and/or intron 10 retention , and produces a non-functional protein and/or introduces a premature termination codon (PMID: 34697416, 37301908).; SCV006071667: Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 5' splicing donor site. Two publications report experimental evidence that this variant affects mRNA splicing (Wai_2020, Oddsson_2023).; SCV002694485: RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Oddsson, 2023; Wai, 2020; Neuser, 2022).; SCV003920336: RNA studies predict that this variant will impact the protein with altered splicing (Wai 2020 PMID:32123317).
• PP5: Variant 19-49862369-A-G is Pathogenic according to our data. Variant chr19-49862369-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 206401.

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.1029+2T>C		splice_donor 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.1029+2T>C		splice_donor intron	N/A	ENSP00000323511.2	Q96T60-1
	PNKP	ENST00000596014.5	TSL:1	c.1029+2T>C		splice_donor intron	N/A	ENSP00000472300.1	Q96T60-1
	PNKP	ENST00000593946.5	TSL:1	n.*956+2T>C		splice_donor intron	N/A	ENSP00000468896.1	M0QX49

Frequencies

GnomAD3 genomes AF: 0.00109 AC: 157 AN: 144138 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000203

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000602

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000236

Gnomad FIN AF: 0.00200

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00195

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00106 AC: 158 AN: 149072 AF XY: 0.00109

Gnomad AFR exome AF: 0.000525

Gnomad AMR exome AF: 0.000328

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00135

Gnomad NFE exome AF: 0.00212

Gnomad OTH exome AF: 0.000943

GnomAD4 exome AF: 0.00187 AC: 2120 AN: 1136252 Hom.: 0 Cov.: 34 AF XY: 0.00179 AC XY: 1016 AN XY: 567000

African (AFR) AF: 0.000156 AC: 4 AN: 25714

American (AMR) AF: 0.000385 AC: 13 AN: 33732

Ashkenazi Jewish (ASJ) AF: 0.000139 AC: 3 AN: 21546

East Asian (EAS) AF: 0.00 AC: 0 AN: 29442

South Asian (SAS) AF: 0.0000674 AC: 5 AN: 74186

European-Finnish (FIN) AF: 0.00130 AC: 54 AN: 41656

Middle Eastern (MID) AF: 0.000263 AC: 1 AN: 3802

European-Non Finnish (NFE) AF: 0.00229 AC: 1972 AN: 859300

Other (OTH) AF: 0.00145 AC: 68 AN: 46874

GnomAD4 genome AF: 0.00109 AC: 157 AN: 144240 Hom.: 0 Cov.: 32 AF XY: 0.00115 AC XY: 81 AN XY: 70546

African (AFR) AF: 0.000202 AC: 8 AN: 39558

American (AMR) AF: 0.00 AC: 0 AN: 14670

Ashkenazi Jewish (ASJ) AF: 0.000602 AC: 2 AN: 3324

East Asian (EAS) AF: 0.00 AC: 0 AN: 4634

South Asian (SAS) AF: 0.000237 AC: 1 AN: 4228

European-Finnish (FIN) AF: 0.00200 AC: 19 AN: 9504

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00195 AC: 127 AN: 65136

Other (OTH) AF: 0.00 AC: 0 AN: 2028

Alfa AF: 0.00153 Hom.: 0

Bravo AF: 0.000854

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00123 AC: 10

ExAC AF: 0.000272 AC: 27

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
9	-	-	Microcephaly, seizures, and developmental delay (9)
9	-	-	not provided (9)
3	-	-	Ataxia - oculomotor apraxia type 4 (3)
1	-	-	Abnormal cerebral morphology (1)
1	-	-	Charcot-Marie-Tooth disease type 2B2;C3150667:Microcephaly, seizures, and developmental delay;C4225397:Ataxia - oculomotor apraxia type 4 (1)
1	-	-	Developmental and epileptic encephalopathy, 12 (1)
1	-	-	Inborn genetic diseases (1)
-	1	-	Microcephaly (1)
1	-	-	Microcephaly, seizures, and developmental delay;C4225397:Ataxia - oculomotor apraxia type 4 (1)
-	1	-	not specified (1)
-	1	-	PNKP-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Uncertain	0.050
CADD	Uncertain	25
DANN	Uncertain	0.99
Eigen	Pathogenic	0.96
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Uncertain	0.92	D
PhyloP100		3.2
GERP RS		5.1
Mutation Taster		=3/97	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
Splicevardb		3.0
SpliceAI score (max)		0.93		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.93		Position offset: 2

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

Other links and lift over

dbSNP: rs199919568; hg19: chr19-50365626;