rs541604147

Variant names:

• chr19-49861518-G-A
• rs541604147
• NM_007254.4:c.1387-8C>T

Your query was ambiguous. Multiple possible variants found:

• chr19-49861518-G-A
• chr19-49861518-G-T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6_Moderate

The NM_007254.4(PNKP):​c.1387-8C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000104 in 1,439,684 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0000071 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: PNKP NM_007254.4 splice_region, intron
• Scores: Splicing: ADA: 0.00003548
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.747
• Publications: 0 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: ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 19-49861518-G-A is Benign according to our data. Variant chr19-49861518-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 487229.Status of the report is criteria_provided_single_submitter, 1 stars.

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.1387-8C>T		splice_region 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.1387-8C>T		splice_region intron	N/A	ENSP00000323511.2
	PNKP	ENST00000596014.5	TSL:1	c.1387-8C>T		splice_region intron	N/A	ENSP00000472300.1
	PNKP	ENST00000593946.5	TSL:1	n.*1314-8C>T		splice_region intron	N/A	ENSP00000468896.1

Frequencies

GnomAD3 genomes AF: 0.00000709 AC: 1 AN: 141014 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000154

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000108 AC: 14 AN: 1298670 Hom.: 0 Cov.: 35 AF XY: 0.0000109 AC XY: 7 AN XY: 645000

African (AFR) AF: 0.00 AC: 0 AN: 28844

American (AMR) AF: 0.00 AC: 0 AN: 40136

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20726

East Asian (EAS) AF: 0.00 AC: 0 AN: 26866

South Asian (SAS) AF: 0.00 AC: 0 AN: 84600

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4924

European-Non Finnish (NFE) AF: 0.0000139 AC: 14 AN: 1003628

Other (OTH) AF: 0.00 AC: 0 AN: 50328

GnomAD4 genome AF: 0.00000709 AC: 1 AN: 141014 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 68262

African (AFR) AF: 0.00 AC: 0 AN: 38776

American (AMR) AF: 0.00 AC: 0 AN: 13860

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3350

East Asian (EAS) AF: 0.00 AC: 0 AN: 4260

South Asian (SAS) AF: 0.00 AC: 0 AN: 4024

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.0000154 AC: 1 AN: 65012

Other (OTH) AF: 0.00 AC: 0 AN: 1950

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Developmental and epileptic encephalopathy, 12 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.11
DANN	Benign	0.63
PhyloP100		-0.75
PromoterAI		-0.0052	Neutral

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000035
dbscSNV1_RF	Benign	0.0040
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: rs541604147; hg19: chr19-50364775;