19-49863956-A-G

Variant names:

• chr19-49863956-A-G
• rs587784370
• NM_007254.4:c.744+8T>C

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP6

The NM_007254.4(PNKP):​c.744+8T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: PNKP NM_007254.4 splice_region, intron
• Scores: Splicing: ADA: 0.00004693
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -0.226
• Publications: 0 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: 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

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 19-49863956-A-G is Benign according to our data. Variant chr19-49863956-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 159800. Variant chr19-49863956-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 159800. Variant chr19-49863956-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 159800. Variant chr19-49863956-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 159800. Variant chr19-49863956-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 159800. Variant chr19-49863956-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 159800. Variant chr19-49863956-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 159800. Variant chr19-49863956-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 159800. Variant chr19-49863956-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 159800. Variant chr19-49863956-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 159800. Variant chr19-49863956-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 159800. Variant chr19-49863956-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 159800. Variant chr19-49863956-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 159800. Variant chr19-49863956-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 159800. Variant chr19-49863956-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 159800. Variant chr19-49863956-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 159800. Variant chr19-49863956-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 159800. Variant chr19-49863956-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 159800. Variant chr19-49863956-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 159800. Variant chr19-49863956-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 159800. Variant chr19-49863956-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 159800. Variant chr19-49863956-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 159800.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PNKP	NM_007254.4	c.744+8T>C		splice_region_variant, intron_variant	Intron 7 of 16	ENST00000322344.8	NP_009185.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PNKP	ENST00000322344.8	c.744+8T>C		splice_region_variant, intron_variant	Intron 7 of 16	1	NM_007254.4	ENSP00000323511.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Microcephaly, seizures, and developmental delay Uncertain:1

Mar 24, 2014

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Developmental and epileptic encephalopathy, 12 Benign:1

Oct 22, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	8.1
DANN	Benign	0.71
PhyloP100		-0.23

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000047
dbscSNV1_RF	Benign	0.0
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs587784370; hg19: chr19-50367213;