rs3739177

Variant names:

• chr19-49865596-C-T
• rs3739177
• NM_007254.4:c.199-170G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_007254.4(PNKP):​c.199-170G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0749 in 547,908 control chromosomes in the GnomAD database, including 1,766 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.070 (376 hom., cov: 30)
  • Exomes 𝑓: 0.077 (1390 hom.)
• Consequence: PNKP NM_007254.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.43
• Publications: 5 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 19-49865596-C-T is Benign according to our data. Variant chr19-49865596-C-T is described in ClinVar as Benign. ClinVar VariationId is 667945.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0805 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.199-170G>A		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.199-170G>A		intron	N/A	ENSP00000323511.2	Q96T60-1
	PNKP	ENST00000596014.5	TSL:1	c.199-170G>A		intron	N/A	ENSP00000472300.1	Q96T60-1
	PNKP	ENST00000593946.5	TSL:1	n.*126-170G>A		intron	N/A	ENSP00000468896.1	M0QX49

Frequencies

GnomAD3 genomes AF: 0.0698 AC: 10200 AN: 146068 Hom.: 376 Cov.: 30

Gnomad AFR AF: 0.0640

Gnomad AMI AF: 0.0280

Gnomad AMR AF: 0.0613

Gnomad ASJ AF: 0.0711

Gnomad EAS AF: 0.000789

Gnomad SAS AF: 0.0829

Gnomad FIN AF: 0.0525

Gnomad MID AF: 0.113

Gnomad NFE AF: 0.0823

Gnomad OTH AF: 0.0609

GnomAD4 exome AF: 0.0768 AC: 30846 AN: 401774 Hom.: 1390 AF XY: 0.0774 AC XY: 16320 AN XY: 210728

African (AFR) AF: 0.0659 AC: 722 AN: 10956

American (AMR) AF: 0.0527 AC: 793 AN: 15036

Ashkenazi Jewish (ASJ) AF: 0.0723 AC: 911 AN: 12600

East Asian (EAS) AF: 0.000253 AC: 7 AN: 27702

South Asian (SAS) AF: 0.0929 AC: 3506 AN: 37742

European-Finnish (FIN) AF: 0.0670 AC: 1870 AN: 27894

Middle Eastern (MID) AF: 0.128 AC: 228 AN: 1784

European-Non Finnish (NFE) AF: 0.0857 AC: 20958 AN: 244478

Other (OTH) AF: 0.0785 AC: 1851 AN: 23582

GnomAD4 genome AF: 0.0698 AC: 10199 AN: 146134 Hom.: 376 Cov.: 30 AF XY: 0.0688 AC XY: 4866 AN XY: 70736

African (AFR) AF: 0.0639 AC: 2498 AN: 39098

American (AMR) AF: 0.0612 AC: 869 AN: 14210

Ashkenazi Jewish (ASJ) AF: 0.0711 AC: 244 AN: 3434

East Asian (EAS) AF: 0.000791 AC: 4 AN: 5060

South Asian (SAS) AF: 0.0835 AC: 383 AN: 4586

European-Finnish (FIN) AF: 0.0525 AC: 486 AN: 9256

Middle Eastern (MID) AF: 0.109 AC: 30 AN: 276

European-Non Finnish (NFE) AF: 0.0823 AC: 5537 AN: 67282

Other (OTH) AF: 0.0603 AC: 123 AN: 2040

Alfa AF: 0.0791 Hom.: 98

Bravo AF: 0.0674

Asia WGS AF: 0.0370 AC: 127 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	5.3
DANN	Benign	0.59
PhyloP100		1.4
PromoterAI		-0.0042	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
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

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

Other links and lift over

dbSNP: rs3739177;

hg19: chr19-50368853;