rs141506076

Positions:

• chr2-218341569-G-A
• chr2-218341569-G-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_015488.5(PNKD):​c.560G>A​(p.Arg187Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000652 in 1,602,846 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R187W) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00093 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00062 (4 hom.)
• Consequence: PNKD NM_015488.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.12

Genes affected

PNKD (HGNC:9153): (PNKD metallo-beta-lactamase domain containing) This gene is thought to play a role in the regulation of myofibrillogenesis. Mutations in this gene have been associated with the movement disorder paroxysmal non-kinesigenic dyskinesia. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2010]

CATIP-AS2 (HGNC:41079): (CATIP antisense RNA 2)

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0057805777).
• BP6: Variant 2-218341569-G-A is Benign according to our data. Variant chr2-218341569-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 334320.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PNKD	NM_015488.5	c.560G>A	p.Arg187Gln	missense_variant	6/10	ENST00000273077.9
CATIP-AS2	NR_125777.1	n.120+9591C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PNKD	ENST00000273077.9	c.560G>A	p.Arg187Gln	missense_variant	6/10	1	NM_015488.5
CATIP-AS2	ENST00000411433.1	n.120+9591C>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.000933 AC: 142 AN: 152176 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0108

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00584

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000294

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.00162 AC: 371 AN: 228474 Hom.: 2 AF XY: 0.00153 AC XY: 190 AN XY: 123866

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000181

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0121

Gnomad SAS exome AF: 0.000179

Gnomad FIN exome AF: 0.00497

Gnomad NFE exome AF: 0.000412

Gnomad OTH exome AF: 0.00251

GnomAD4 exome AF: 0.000623 AC: 903 AN: 1450552 Hom.: 4 Cov.: 31 AF XY: 0.000597 AC XY: 430 AN XY: 720380

Gnomad4 AFR exome AF: 0.0000301

Gnomad4 AMR exome AF: 0.000183

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0118

Gnomad4 SAS exome AF: 0.000298

Gnomad4 FIN exome AF: 0.00498

Gnomad4 NFE exome AF: 0.0000867

Gnomad4 OTH exome AF: 0.000818

GnomAD4 genome AF: 0.000932 AC: 142 AN: 152294 Hom.: 0 Cov.: 32 AF XY: 0.00137 AC XY: 102 AN XY: 74472

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0108

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00584

Gnomad4 NFE AF: 0.000294

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.000763 Hom.: 1

Bravo AF: 0.000748

ExAC AF: 0.00158 AC: 191

Asia WGS AF: 0.00751 AC: 26 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Paroxysmal nonkinesigenic dyskinesia 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 05, 2020

- -

Paroxysmal nonkinesigenic dyskinesia Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 22, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	21
DANN	Benign	0.97
DEOGEN2	Benign	0.23	T;.;.
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.11
FATHMM_MKL	Benign	0.56	D
LIST_S2	Benign	0.82	T;T;T
MetaRNN	Benign	0.0058	T;T;T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	0.19	N;.;.
MutationTaster	Benign	0.77	N;N;N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.030	N;N;N
REVEL	Benign	0.15
Sift	Benign	0.49	T;T;T
Sift4G	Benign	0.68	T;T;T
Polyphen		0.0010	B;B;.
Vest4		0.18
MVP		0.40
MPC		0.16
ClinPred		0.013	T
GERP RS		3.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.058
gMVP		0.51

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

Publications

LitVar

Other links and lift over

dbSNP: rs141506076; hg19: chr2-219206292;