rs578207030

Variant names:

• chr19-49861766-C-T
• rs578207030
• NM_007254.4:c.1298+6G>A

Your query was ambiguous. Multiple possible variants found:

• chr19-49861766-C-T
• chr19-49861766-C-A
• chr19-49861766-C-G

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_007254.4(PNKP):​c.1298+6G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000402 in 1,565,992 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 𝑓 0.000059 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000038 (0 hom.)
• Consequence: PNKP NM_007254.4 splice_region, intron
• Scores: Splicing: ADA: 0.00005058
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:2 O:1
• Conservation: PhyloP100: -3.81
• 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: Laboratory for Molecular Medicine, G2P, Orphanet
• microcephaly, seizures, and developmental delay

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen
• 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 -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 19-49861766-C-T is Benign according to our data. Variant chr19-49861766-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 138721.

Variant Effect in Transcripts

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

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PNKP	NM_007254.4	MANE Select	c.1298+6G>A		splice_region intron	N/A	NP_009185.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PNKP	ENST00000322344.8	TSL:1 MANE Select	c.1298+6G>A		splice_region intron	N/A	ENSP00000323511.2	Q96T60-1
	PNKP	ENST00000596014.5	TSL:1	c.1298+6G>A		splice_region intron	N/A	ENSP00000472300.1	Q96T60-1
	PNKP	ENST00000593946.5	TSL:1	n.*1225+6G>A		splice_region intron	N/A	ENSP00000468896.1	M0QX49

Frequencies

GnomAD3 genomes AF: 0.0000660 AC: 10 AN: 151408 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000246

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000524

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000971 AC: 17 AN: 174996 AF XY: 0.0000744

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000523

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000137

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000382 AC: 54 AN: 1414472 Hom.: 0 Cov.: 38 AF XY: 0.0000429 AC XY: 30 AN XY: 699800

African (AFR) AF: 0.0000311 AC: 1 AN: 32124

American (AMR) AF: 0.000690 AC: 26 AN: 37706

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25464

East Asian (EAS) AF: 0.00 AC: 0 AN: 36646

South Asian (SAS) AF: 0.0000742 AC: 6 AN: 80890

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48800

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5700

European-Non Finnish (NFE) AF: 0.0000129 AC: 14 AN: 1088568

Other (OTH) AF: 0.000120 AC: 7 AN: 58574

GnomAD4 genome AF: 0.0000594 AC: 9 AN: 151520 Hom.: 0 Cov.: 32 AF XY: 0.0000405 AC XY: 3 AN XY: 74128

African (AFR) AF: 0.0000245 AC: 1 AN: 40826

American (AMR) AF: 0.000458 AC: 7 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68010

Other (OTH) AF: 0.00 AC: 0 AN: 2104

Alfa AF: 0.000103 Hom.: 0

Bravo AF: 0.0000869

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	Ataxia - oculomotor apraxia type 4 (1)
-	1	-	Developmental and epileptic encephalopathy, 12 (1)
-	1	-	not provided (1)
-	-	1	not specified (1)
-	-	1	PNKP-related disorder (1)
-	-	-	Microcephaly, seizures, and developmental delay;C4225397:Ataxia - oculomotor apraxia type 4 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.028
DANN	Benign	0.80
PhyloP100		-3.8
PromoterAI		-0.083	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000051
dbscSNV1_RF	Benign	0.0080
SpliceAI score (max)		0.020		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: rs578207030; hg19: chr19-50365023;