rs34472250

Variant names:

• chr19-49865209-C-T
• rs34472250
• NM_007254.4:c.416G>A

Your query was ambiguous. Multiple possible variants found:

• chr19-49865209-C-T
• chr19-49865209-C-G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_007254.4(PNKP):​c.416G>A​(p.Arg139His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00292 in 1,614,214 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. R139R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0018 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0030 (7 hom.)
• Consequence: PNKP NM_007254.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:9
• Conservation: PhyloP100: 0.160
• Publications: 11 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0042013526).
• BP6: Variant 19-49865209-C-T is Benign according to our data. Variant chr19-49865209-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 159794.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00182 (277/152346) while in subpopulation NFE AF = 0.00287 (195/68032). AF 95% confidence interval is 0.00254. There are 0 homozygotes in GnomAd4. There are 122 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 7 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.416G>A	p.Arg139His	missense	Exon 4 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.416G>A	p.Arg139His	missense	Exon 4 of 17	ENSP00000323511.2	Q96T60-1
	PNKP	ENST00000596014.5	TSL:1	c.416G>A	p.Arg139His	missense	Exon 3 of 16	ENSP00000472300.1	Q96T60-1
	PNKP	ENST00000593946.5	TSL:1	n.*343G>A		non_coding_transcript_exon	Exon 3 of 16	ENSP00000468896.1	M0QX49

Frequencies

GnomAD3 genomes AF: 0.00182 AC: 277 AN: 152228 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000699

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00196

Gnomad ASJ AF: 0.00230

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00287

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.00194 AC: 487 AN: 251392 AF XY: 0.00218

Gnomad AFR exome AF: 0.000984

Gnomad AMR exome AF: 0.000723

Gnomad ASJ exome AF: 0.00109

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000601

Gnomad NFE exome AF: 0.00308

Gnomad OTH exome AF: 0.00212

GnomAD4 exome AF: 0.00304 AC: 4437 AN: 1461868 Hom.: 7 Cov.: 34 AF XY: 0.00295 AC XY: 2148 AN XY: 727236

African (AFR) AF: 0.000418 AC: 14 AN: 33478

American (AMR) AF: 0.000894 AC: 40 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00157 AC: 41 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00185 AC: 160 AN: 86256

European-Finnish (FIN) AF: 0.000487 AC: 26 AN: 53418

Middle Eastern (MID) AF: 0.00139 AC: 8 AN: 5768

European-Non Finnish (NFE) AF: 0.00362 AC: 4029 AN: 1111994

Other (OTH) AF: 0.00197 AC: 119 AN: 60394

GnomAD4 genome AF: 0.00182 AC: 277 AN: 152346 Hom.: 0 Cov.: 32 AF XY: 0.00164 AC XY: 122 AN XY: 74498

African (AFR) AF: 0.000697 AC: 29 AN: 41586

American (AMR) AF: 0.00196 AC: 30 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00230 AC: 8 AN: 3472

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5182

South Asian (SAS) AF: 0.00186 AC: 9 AN: 4834

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10622

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

European-Non Finnish (NFE) AF: 0.00287 AC: 195 AN: 68032

Other (OTH) AF: 0.00142 AC: 3 AN: 2114

Alfa AF: 0.00260 Hom.: 3

Bravo AF: 0.00207

TwinsUK AF: 0.00297 AC: 11

ALSPAC AF: 0.00259 AC: 10

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.00291 AC: 25

ExAC AF: 0.00201 AC: 244

EpiCase AF: 0.00311

EpiControl AF: 0.00332

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	3	3	not provided (6)
-	1	1	Microcephaly, seizures, and developmental delay (2)
-	-	2	not specified (2)
-	-	1	Charcot-Marie-Tooth disease type 2B2;C3150667:Microcephaly, seizures, and developmental delay;C4225397:Ataxia - oculomotor apraxia type 4 (1)
-	-	1	Developmental and epileptic encephalopathy, 12 (1)
-	1	-	Inborn genetic diseases (1)
-	1	-	Microcephaly, seizures, and developmental delay;C4225397:Ataxia - oculomotor apraxia type 4 (1)
-	-	1	PNKP-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.033	T
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.61
FATHMM_MKL	Benign	0.062	N
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.0042	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		0.16
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.71	N
REVEL	Benign	0.059
Sift	Benign	0.23	T
Sift4G	Benign	0.076	T
Polyphen		0.82	P
Vest4		0.22
MVP		0.55
MPC		0.20
ClinPred		0.0099	T
GERP RS		3.1
PromoterAI		-0.055	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.064
gMVP		0.27
Mutation Taster		=99/1	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: rs34472250; hg19: chr19-50368466; COSMIC: COSV55586208; COSMIC: COSV55586208;