chr19-49862113-G-C

Variant names:

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

GermlineCancer (beta)

Variant summary

Our verdict is Likely benign.

-2 Likely Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -2 classification points (ACMG Germline Pathogenicity v2019). PM2BP4_Strong

The NM_007254.4(PNKP):c.1127-8C>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. In-silico predictor (BayesDel (noAF)) classifies this variant as likely benign. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PNKP NM_007254.4 splice_region, intron
• Scores: Splicing: ADA: 0.02848
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.562
• 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, 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: Likely_benign. The variant received -2 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM2Absent/extremely low in population databases		Absent from gnomAD (AD/XL gene) — PM2; Absent from gnomAD at well-covered site (MOI: AD+AR) (base 0.0001, raised to 0.0005 by highest known P/LP ClinVar AF 0.00178) — PM2 moderate.
	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).

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>G	splice_regionintron	Intron 12 of 16	Prot: NP_009185.2

PNKP NM_007254.4

MANE Select

HGVSc / HGVSpc.1127-8C>G

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>G	splice_regionintron	Intron 12 of 16	Prot: ENSP00000323511.2 UniProt:
	PNKP ENST00000596014.5	TSL:1	c.1127-8C>G	splice_regionintron	Intron 11 of 15	Prot: ENSP00000472300.1 UniProt:
	PNKP ENST00000593946.5	TSL:1	n.*1054-8C>G	splice_regionintron	Intron 11 of 15	Prot: ENSP00000468896.1 UniProt:

PNKP ENST00000322344.8

TSL:1MANE Select

HGVSc / HGVSpc.1127-8C>G

Exon rankIntron 12 of 16

splice_regionintron

Prot: ENSP00000323511.2UniProt: Q96T60-1

PNKP ENST00000596014.5

TSL:1

HGVSc / HGVSpc.1127-8C>G

Exon rankIntron 11 of 15

splice_regionintron

Prot: ENSP00000472300.1UniProt: Q96T60-1

PNKP ENST00000593946.5

TSL:1

HGVSc / HGVSpn.*1054-8C>G

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 3 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:32
GnomAD4 exome	AF:	AC:	Hom:	AN:	Cov:34
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32

Showing 3 sources

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Uncertain	15
BayesDel_noAF	Benign	-0.75
CADD	Benign	9.9
DANN	Benign	0.82
GPN-Star LLR	N/A	-0.20
GPN-Star score	N/A	0.20
PhyloP100	Benign	0.56
PromoterAI	N/A	-0.016	Neutral
RBP_binding_hub_radar	N/A	0.0
RBP_regulation_power_radar	N/A	1.1

Showing 10 of 10 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
dbscSNV1_ADA	Benign	0.028
dbscSNV1_RF	Benign	0.32
DS_AL_spliceai	Uncertain	0.21	Position offset: -8
Pangolin (max)	Uncertain	0.35
Pangolin gain	Benign	0.18	Position offset: 21
Pangolin loss	Uncertain	0.35	Position offset: -8
SpliceAI score (max)	Uncertain	0.21	Details are displayed if max score is > 0.2

Showing 7 of 7 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