rs3739205

Variant names:

• chr19-49861890-AC-A
• rs3739205
• NM_007254.4:c.1189-10delG

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_007254.4(PNKP):​c.1189-10delG variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00464 in 1,585,660 control chromosomes in the GnomAD database, including 268 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.024 (128 hom., cov: 32)
  • Exomes 𝑓: 0.0026 (140 hom.)
• Consequence: PNKP NM_007254.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -1.62
• Publications: 1 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: Benign. The variant received -16 ACMG points.

• BP6: Variant 19-49861890-AC-A is Benign according to our data. Variant chr19-49861890-AC-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 95477.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.081 is higher than 0.05.

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.1189-10delG		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.1189-10delG		intron	N/A	ENSP00000323511.2	Q96T60-1
	PNKP	ENST00000596014.5	TSL:1	c.1189-10delG		intron	N/A	ENSP00000472300.1	Q96T60-1
	PNKP	ENST00000593946.5	TSL:1	n.*1116-10delG		intron	N/A	ENSP00000468896.1	M0QX49

Frequencies

GnomAD3 genomes AF: 0.0241 AC: 3664 AN: 151896 Hom.: 128 Cov.: 32

Gnomad AFR AF: 0.0832

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0109

Gnomad ASJ AF: 0.00231

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.0187

GnomAD2 exomes AF: 0.00662 AC: 1362 AN: 205710 AF XY: 0.00502

Gnomad AFR exome AF: 0.0912

Gnomad AMR exome AF: 0.00558

Gnomad ASJ exome AF: 0.00286

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000218

Gnomad OTH exome AF: 0.00317

GnomAD4 exome AF: 0.00257 AC: 3683 AN: 1433646 Hom.: 140 Cov.: 36 AF XY: 0.00226 AC XY: 1610 AN XY: 712046

African (AFR) AF: 0.0856 AC: 2815 AN: 32890

American (AMR) AF: 0.00587 AC: 238 AN: 40572

Ashkenazi Jewish (ASJ) AF: 0.00217 AC: 56 AN: 25828

East Asian (EAS) AF: 0.00 AC: 0 AN: 38428

South Asian (SAS) AF: 0.000179 AC: 15 AN: 83832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46990

Middle Eastern (MID) AF: 0.00279 AC: 16 AN: 5730

European-Non Finnish (NFE) AF: 0.000137 AC: 151 AN: 1099870

Other (OTH) AF: 0.00659 AC: 392 AN: 59506

GnomAD4 genome AF: 0.0242 AC: 3679 AN: 152014 Hom.: 128 Cov.: 32 AF XY: 0.0234 AC XY: 1742 AN XY: 74322

African (AFR) AF: 0.0833 AC: 3446 AN: 41366

American (AMR) AF: 0.0109 AC: 166 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00231 AC: 8 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5156

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000235 AC: 16 AN: 67974

Other (OTH) AF: 0.0185 AC: 39 AN: 2112

Alfa AF: 0.00182 Hom.: 1

Bravo AF: 0.0278

Asia WGS AF: 0.00577 AC: 20 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	Microcephaly, seizures, and developmental delay (2)
-	-	1	Developmental and epileptic encephalopathy, 12 (1)
-	-	1	Epileptic encephalopathy (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-1.6
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs3739205; hg19: chr19-50365147;