rs145904995

Variant names:

• chr19-49864236-C-T
• rs145904995
• NM_007254.4:c.579G>A

Your query was ambiguous. Multiple possible variants found:

• chr19-49864236-C-T
• chr19-49864236-C-G

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 1P and 16B. PP3 BP6_Very_Strong BS1 BS2

The NM_007254.4(PNKP):​c.579G>A​(p.Arg193Arg) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00297 in 1,614,146 control chromosomes in the GnomAD database, including 61 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0025 (5 hom., cov: 33)
  • Exomes 𝑓: 0.0030 (56 hom.)
• Consequence: PNKP NM_007254.4 splice_region, synonymous
• Scores: Splicing: ADA: 0.9996
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 3.53
• 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: 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 -15 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.
• BP6: Variant 19-49864236-C-T is Benign according to our data. Variant chr19-49864236-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 95484.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00246 (374/152314) while in subpopulation SAS AF = 0.0141 (68/4824). AF 95% confidence interval is 0.0114. There are 5 homozygotes in GnomAd4. There are 193 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 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.579G>A	p.Arg193Arg	splice_region synonymous	Exon 6 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.579G>A	p.Arg193Arg	splice_region synonymous	Exon 6 of 17	ENSP00000323511.2	Q96T60-1
	PNKP	ENST00000596014.5	TSL:1	c.579G>A	p.Arg193Arg	splice_region synonymous	Exon 5 of 16	ENSP00000472300.1	Q96T60-1
	PNKP	ENST00000593946.5	TSL:1	n.*506G>A		splice_region non_coding_transcript_exon	Exon 5 of 16	ENSP00000468896.1	M0QX49

Frequencies

GnomAD3 genomes AF: 0.00247 AC: 376 AN: 152196 Hom.: 5 Cov.: 33

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00124

Gnomad ASJ AF: 0.0418

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0145

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.00165

Gnomad OTH AF: 0.00621

GnomAD2 exomes AF: 0.00438 AC: 1101 AN: 251440 AF XY: 0.00504

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.00133

Gnomad ASJ exome AF: 0.0430

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.000185

Gnomad NFE exome AF: 0.00201

Gnomad OTH exome AF: 0.00749

GnomAD4 exome AF: 0.00303 AC: 4423 AN: 1461832 Hom.: 56 Cov.: 33 AF XY: 0.00339 AC XY: 2464 AN XY: 727220

African (AFR) AF: 0.00102 AC: 34 AN: 33480

American (AMR) AF: 0.00159 AC: 71 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0434 AC: 1135 AN: 26134

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39698

South Asian (SAS) AF: 0.0118 AC: 1020 AN: 86258

European-Finnish (FIN) AF: 0.000300 AC: 16 AN: 53398

Middle Eastern (MID) AF: 0.0135 AC: 78 AN: 5768

European-Non Finnish (NFE) AF: 0.00156 AC: 1731 AN: 1111980

Other (OTH) AF: 0.00555 AC: 335 AN: 60392

GnomAD4 genome AF: 0.00246 AC: 374 AN: 152314 Hom.: 5 Cov.: 33 AF XY: 0.00259 AC XY: 193 AN XY: 74474

African (AFR) AF: 0.000192 AC: 8 AN: 41560

American (AMR) AF: 0.00124 AC: 19 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0418 AC: 145 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.0141 AC: 68 AN: 4824

European-Finnish (FIN) AF: 0.000282 AC: 3 AN: 10624

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.00165 AC: 112 AN: 68028

Other (OTH) AF: 0.00615 AC: 13 AN: 2114

Alfa AF: 0.00353 Hom.: 8

Bravo AF: 0.00232

Asia WGS AF: 0.00606 AC: 21 AN: 3478

EpiCase AF: 0.00289

EpiControl AF: 0.00332

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	2	not provided (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 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_noAF	Benign	-0.14
CADD	Benign	20
DANN	Benign	0.95
PhyloP100		3.5
Mutation Taster		=12/88	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		0.34		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.34		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs145904995; hg19: chr19-50367493; COSMIC: COSV55587900; COSMIC: COSV55587900;