NM_007254.4:c.1127-8C>T

Variant names:

• chr19-49862113-G-A
• rs3739203
• NM_007254.4:c.1127-8C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_007254.4(PNKP):​c.1127-8C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00877 in 1,614,094 control chromosomes in the GnomAD database, including 86 homozygotes. 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0087 (7 hom., cov: 32)
  • Exomes 𝑓: 0.0088 (79 hom.)
• Consequence: PNKP NM_007254.4 splice_region, intron
• Scores: Splicing: ADA: 0.01320
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 0.562
• Publications: 3 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant 19-49862113-G-A is Benign according to our data. Variant chr19-49862113-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 95476.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00868 (1322/152272) while in subpopulation AMR AF = 0.00993 (152/15302). AF 95% confidence interval is 0.00902. There are 7 homozygotes in GnomAd4. There are 566 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 7 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PNKP	NM_007254.4	c.1127-8C>T		splice_region_variant, intron_variant	Intron 12 of 16	ENST00000322344.8	NP_009185.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PNKP	ENST00000322344.8	c.1127-8C>T		splice_region_variant, intron_variant	Intron 12 of 16	1	NM_007254.4	ENSP00000323511.2

Frequencies

GnomAD3 genomes AF: 0.00870 AC: 1323 AN: 152154 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.00949

Gnomad AMI AF: 0.0373

Gnomad AMR AF: 0.00995

Gnomad ASJ AF: 0.0121

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000827

Gnomad FIN AF: 0.00104

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.00963

Gnomad OTH AF: 0.0110

GnomAD2 exomes AF: 0.00674 AC: 1695 AN: 251374 AF XY: 0.00650

Gnomad AFR exome AF: 0.00942

Gnomad AMR exome AF: 0.00607

Gnomad ASJ exome AF: 0.00943

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00194

Gnomad NFE exome AF: 0.00954

Gnomad OTH exome AF: 0.0112

GnomAD4 exome AF: 0.00878 AC: 12839 AN: 1461822 Hom.: 79 Cov.: 34 AF XY: 0.00861 AC XY: 6259 AN XY: 727216

African (AFR) AF: 0.0104 AC: 349 AN: 33480

American (AMR) AF: 0.00604 AC: 270 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0103 AC: 269 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00146 AC: 126 AN: 86258

European-Finnish (FIN) AF: 0.00215 AC: 115 AN: 53416

Middle Eastern (MID) AF: 0.0123 AC: 71 AN: 5768

European-Non Finnish (NFE) AF: 0.00993 AC: 11037 AN: 1111952

Other (OTH) AF: 0.00997 AC: 602 AN: 60394

GnomAD4 genome AF: 0.00868 AC: 1322 AN: 152272 Hom.: 7 Cov.: 32 AF XY: 0.00760 AC XY: 566 AN XY: 74452

African (AFR) AF: 0.00948 AC: 394 AN: 41542

American (AMR) AF: 0.00993 AC: 152 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0121 AC: 42 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.000828 AC: 4 AN: 4830

European-Finnish (FIN) AF: 0.00104 AC: 11 AN: 10624

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.00963 AC: 655 AN: 68010

Other (OTH) AF: 0.0109 AC: 23 AN: 2114

Alfa AF: 0.00933 Hom.: 3

Bravo AF: 0.00940

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Microcephaly, seizures, and developmental delay Benign:4

Oct 09, 2014

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 31, 2017

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:4

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

-

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jun 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PNKP: BP4, BS2 -

Jan 26, 2018

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:3

May 11, 2012

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: 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. -

Dec 11, 2015

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 27, 2012

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Developmental and epileptic encephalopathy, 12 Benign:1

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: 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	-0.73
CADD	Benign	5.8
DANN	Benign	0.91
PhyloP100		0.56
PromoterAI		0.0014	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.013
dbscSNV1_RF	Benign	0.080
SpliceAI score (max)		0.0		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: rs3739203; hg19: chr19-50365370;