chr19-49862113-G-A

Variant names:

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

GermlineCancer (beta)

Variant summary

Our verdict is Benign.

<-10 Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -12 classification points (ACMG Germline Pathogenicity v2019). BS2BP4_StrongBP6_Strong

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 cumulative frequency of 0.00877 (AC=14,161) in the gnomAD database across 1,614,094 control chromosomes, including 86 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.01. In-silico predictor (BayesDel (noAF)) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign/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:14
• 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, STRONG, SUPPORTIVE Submitted by: Laboratory for Molecular Medicine, Orphanet, G2P, PanelApp Australia
• microcephaly, seizures, and developmental delay

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen
• Charcot-Marie-Tooth disease type 2B2

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: PanelApp Australia, Orphanet, Labcorp Genetics (formerly Invitae)
• genetic developmental and epileptic encephalopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Benign. The variant received -12 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	BP4Computational evidence suggests no impact		Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Strong).
	BP6Reputable source reports benign		ClinVar 2-star benign — strong (BP6); ClinVar submissions overwhelmingly benign (≥10 total, ≥80% B/LB, <10% P/LP) — strong (BP6, count-based); ClinVar germline classification: Benign/Likely Benign, 2 star(s). ClinVar submissions strongly and reliably favor benignity (14/14 total B/LB).
	BS2Observed in healthy adult		≥2 homozygotes in gnomAD — observed in healthy adults (BS2); GnomAD homozygous count = 86.; Very high cumulative gnomAD AC = 14161 (any gene).

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_007254.4. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	PNKP NM_007254.4	MANE Select	c.1127-8C>T	splice_regionintron	Intron 12 of 16	Prot: NP_009185.2

PNKP NM_007254.4

MANE Select

HGVSc / HGVSpc.1127-8C>T

Exon rankIntron 12 of 16

splice_regionintron

Prot: NP_009185.2

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	PNKP ENST00000322344.8	TSL:1MANE Select	c.1127-8C>T	splice_regionintron	Intron 12 of 16	Prot: ENSP00000323511.2 UniProt:
	PNKP ENST00000596014.5	TSL:1	c.1127-8C>T	splice_regionintron	Intron 11 of 15	Prot: ENSP00000472300.1 UniProt:
	PNKP ENST00000593946.5	TSL:1	n.*1054-8C>T	splice_regionintron	Intron 11 of 15	Prot: ENSP00000468896.1 UniProt:

PNKP ENST00000322344.8

TSL:1MANE Select

HGVSc / HGVSpc.1127-8C>T

Exon rankIntron 12 of 16

splice_regionintron

Prot: ENSP00000323511.2UniProt: Q96T60-1

PNKP ENST00000596014.5

TSL:1

HGVSc / HGVSpc.1127-8C>T

Exon rankIntron 11 of 15

splice_regionintron

Prot: ENSP00000472300.1UniProt: Q96T60-1

PNKP ENST00000593946.5

TSL:1

HGVSc / HGVSpn.*1054-8C>T

Exon rankIntron 11 of 15

splice_regionintron

Prot: ENSP00000468896.1UniProt: M0QX49

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 6 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.00870	AC:1323	Hom:7	AN:152154	Cov:32
GnomAD2 exomes	AF: 0.00674	AC:1695	Hom:	AN:251374	Cov:
GnomAD4 exome	AF: 0.00878	AC:12839	Hom:79	AN:1461822	Cov:34
GnomAD4 genome	AF: 0.00868	AC:1322	Hom:7	AN:152272	Cov:32
TOPMed (Bravo)	AF: 0.00940	AC:	Hom:	AN:	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.00939	AC:714	Hom:4	AN:76016	Cov:
Local & regional cohorts 10 sources Population-specific and national genomic databases
ABraOM SABE-WGS-1171	AF: 0.00854	AC:20	Hom:0	AN:2342	Cov:
ChinaMAP Phase 1	AF: 0.0000985	AC:	Hom:	AN:	Cov:
Denmark Genome	AF: 0.0100	AC:3	Hom:	AN:300	Cov:
ESP6500 (Exome Variant Server)	AF: 0.00923	AC:120	Hom:	AN:13006	Cov:
GenomeAsia100K	AF: 0.00115	AC:4	Hom:	AN:3478	Cov:
Qatari Genome	AF: 0.00570	AC:1	Hom:	AN:176	Cov:
ToMMo 61KJPN (+60KJPN MNV)	AF: 0.0000160	AC:2	Hom:0	AN:122248	Cov:
Turkish Variome	AF: 0.0103	AC:69	Hom:2	AN:6700	Cov:
UK10K	AF: 0.00912	AC:69	Hom:	AN:7562	Cov:
WBBC (Westlake BioBank for Chinese) pilot	AF: 0.000112	AC:1	Hom:0	AN:8960	Cov:

Showing 16 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
ASC(Autism)	0.00738 *	11	1490	0.00834 *	60	7190
BipEx(Bipolar disorder (including schizoaffective))	0.00939	267	28420	0.00870	251	28844
SCHEMA(Schizophrenia)	0.0107	1135	105786	0.0145	2186	151264

Showing 3 cohortsAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	4	Microcephaly, seizures, and developmental delay (4)
-	-	4	not provided (4)
-	-	1	Developmental and epileptic encephalopathy, 12 (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Benign	8.9
BayesDel_noAF	Benign	-0.73
CADD	Benign	5.8
DANN	Benign	0.91
GPN-Star LLR	N/A	-0.32
GPN-Star score	N/A	0.32
Mutation Taster	N/A	99/1	polymorphism
PhyloP100	Benign	0.56
PromoterAI	N/A	0.0014	Neutral
RBP_binding_hub_radar	N/A	0.0
RBP_regulation_power_radar	N/A	1.1

Showing 11 of 11 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
dbscSNV1_ADA	Benign	0.013
dbscSNV1_RF	Benign	0.080
Pangolin (max)	Benign	0.070
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 4 of 4 scores

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs3739203;

hg19: chr19-50365370;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar