chr2-218341575-G-T

Variant names:

• chr2-218341575-G-T
• rs199987826
• NM_015488.5:c.566G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_015488.5(PNKD):​c.566G>T​(p.Arg189Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000691 in 1,447,362 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R189P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: PNKD NM_015488.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.21
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21844593).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015488.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PNKD	NM_015488.5	MANE Select	c.566G>T	p.Arg189Leu	missense	Exon 6 of 10	NP_056303.3
	PNKD	NM_022572.4		c.494G>T	p.Arg165Leu	missense	Exon 5 of 9	NP_072094.1
	CATIP-AS2	NR_125777.1		n.120+9585C>A		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PNKD	ENST00000273077.9	TSL:1 MANE Select	c.566G>T	p.Arg189Leu	missense	Exon 6 of 10	ENSP00000273077.4
	PNKD	ENST00000258362.7	TSL:1	c.494G>T	p.Arg165Leu	missense	Exon 5 of 9	ENSP00000258362.3
	PNKD	ENST00000685415.1		c.683G>T	p.Arg228Leu	missense	Exon 7 of 11	ENSP00000510415.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.91e-7 AC: 1 AN: 1447362 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 718588

African (AFR) AF: 0.00 AC: 0 AN: 33142

American (AMR) AF: 0.00 AC: 0 AN: 43362

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25810

East Asian (EAS) AF: 0.00 AC: 0 AN: 38870

South Asian (SAS) AF: 0.00 AC: 0 AN: 83622

European-Finnish (FIN) AF: 0.0000193 AC: 1 AN: 51740

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5594

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1105472

Other (OTH) AF: 0.00 AC: 0 AN: 59750

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Paroxysmal nonkinesigenic dyskinesia Uncertain:1

Jul 30, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with PNKD-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with leucine at codon 189 of the PNKD protein (p.Arg189Leu). The arginine residue is weakly conserved and there is a moderate physicochemical difference between arginine and leucine. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Uncertain	0.047	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.63	D
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.38
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.90	D
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.22	T
MetaSVM	Uncertain	-0.20	T
MutationAssessor	Benign	0.62	N
PhyloP100		2.2
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-2.0	N
REVEL	Uncertain	0.34
Sift	Benign	0.054	T
Sift4G	Benign	0.14	T
Polyphen		0.015	B
Vest4		0.32
MutPred		0.56		Loss of MoRF binding (P = 0.019)
MVP		0.58
MPC		0.20
ClinPred		0.37	T
GERP RS		1.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.072
gMVP		0.34
Mutation Taster		=86/14	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: rs199987826; hg19: chr2-219206298;