NM_007254.4:c.939T>C

Variant names:

• chr19-49862461-A-G
• rs149731642
• NM_007254.4:c.939T>C

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_007254.4(PNKP):​c.939T>C​(p.Phe313Phe) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00338 in 1,591,856 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0028 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0034 (12 hom.)
• Consequence: PNKP NM_007254.4 splice_region, synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 0.0920
• Publications: 2 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 19-49862461-A-G is Benign according to our data. Variant chr19-49862461-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 138717.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.092 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00277 (422/152212) while in subpopulation NFE AF = 0.00509 (346/67982). AF 95% confidence interval is 0.00465. There are 1 homozygotes in GnomAd4. There are 179 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 12 AR,AD gene

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.939T>C	p.Phe313Phe	splice_region synonymous	Exon 11 of 17	NP_009185.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PNKP	ENST00000322344.8	TSL:1 MANE Select	c.939T>C	p.Phe313Phe	splice_region synonymous	Exon 11 of 17	ENSP00000323511.2	Q96T60-1
	PNKP	ENST00000596014.5	TSL:1	c.939T>C	p.Phe313Phe	splice_region synonymous	Exon 10 of 16	ENSP00000472300.1	Q96T60-1
	PNKP	ENST00000593946.5	TSL:1	n.*866T>C		splice_region non_coding_transcript_exon	Exon 10 of 16	ENSP00000468896.1	M0QX49

Frequencies

GnomAD3 genomes AF: 0.00277 AC: 422 AN: 152094 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000676

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.00461

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000472

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00509

Gnomad OTH AF: 0.00288

GnomAD2 exomes AF: 0.00221 AC: 467 AN: 211452 AF XY: 0.00235

Gnomad AFR exome AF: 0.000161

Gnomad AMR exome AF: 0.000789

Gnomad ASJ exome AF: 0.00204

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000504

Gnomad NFE exome AF: 0.00401

Gnomad OTH exome AF: 0.00243

GnomAD4 exome AF: 0.00344 AC: 4959 AN: 1439644 Hom.: 12 Cov.: 36 AF XY: 0.00341 AC XY: 2435 AN XY: 714134

African (AFR) AF: 0.000363 AC: 12 AN: 33084

American (AMR) AF: 0.000898 AC: 37 AN: 41204

Ashkenazi Jewish (ASJ) AF: 0.00257 AC: 66 AN: 25658

East Asian (EAS) AF: 0.00 AC: 0 AN: 38652

South Asian (SAS) AF: 0.000853 AC: 71 AN: 83206

European-Finnish (FIN) AF: 0.000913 AC: 47 AN: 51468

Middle Eastern (MID) AF: 0.00105 AC: 6 AN: 5730

European-Non Finnish (NFE) AF: 0.00414 AC: 4556 AN: 1101124

Other (OTH) AF: 0.00276 AC: 164 AN: 59518

GnomAD4 genome AF: 0.00277 AC: 422 AN: 152212 Hom.: 1 Cov.: 33 AF XY: 0.00240 AC XY: 179 AN XY: 74430

African (AFR) AF: 0.000674 AC: 28 AN: 41550

American (AMR) AF: 0.00131 AC: 20 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00461 AC: 16 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.000472 AC: 5 AN: 10602

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

European-Non Finnish (NFE) AF: 0.00509 AC: 346 AN: 67982

Other (OTH) AF: 0.00285 AC: 6 AN: 2108

Alfa AF: 0.00346 Hom.: 0

Bravo AF: 0.00253

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	3	Microcephaly, seizures, and developmental delay (3)
-	-	3	not specified (3)
-	-	1	Developmental and epileptic encephalopathy, 12 (1)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Benign	5.4
DANN	Benign	0.76
PhyloP100		0.092
Mutation Taster		=95/5	polymorphism

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

Other links and lift over

dbSNP: rs149731642; hg19: chr19-50365718;