Submissions for variant NM_007254.4(PNKP):c.1298+6G>A

gnomAD frequency: 0.00010  dbSNP: rs578207030

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000127490	SCV000171065	benign	not specified	2013-10-21	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Invitae	RCV000460234	SCV000549897	uncertain significance	Developmental and epileptic encephalopathy, 12	2022-10-13	criteria provided, single submitter	clinical testing	This sequence change falls in intron 14 of the PNKP gene. It does not directly change the encoded amino acid sequence of the PNKP protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs578207030, gnomAD 0.06%). This variant has not been reported in the literature in individuals affected with PNKP-related conditions. ClinVar contains an entry for this variant (Variation ID: 138721). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
New York Genome Center	RCV001588978	SCV001815820	uncertain significance	Ataxia - oculomotor apraxia type 4	2020-09-09	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003952669	SCV004771860	likely benign	PNKP-related condition	2019-07-10	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).