chr2-218270582-G-T

Variant names:

• chr2-218270582-G-T
• rs1553654496
• NM_015488.5:c.47G>T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_015488.5(PNKD):​c.47G>T​(p.Arg16Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PNKD NM_015488.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.08

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PNKD	NM_015488.5	c.47G>T	p.Arg16Ile	missense_variant	Exon 1 of 10	ENST00000273077.9	NP_056303.3
PNKD	NM_001077399.3	c.47G>T	p.Arg16Ile	missense_variant	Exon 1 of 3		NP_001070867.1
PNKD	XM_017003771.2	c.47G>T	p.Arg16Ile	missense_variant	Exon 1 of 9		XP_016859260.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PNKD	ENST00000273077.9	c.47G>T	p.Arg16Ile	missense_variant	Exon 1 of 10	1	NM_015488.5	ENSP00000273077.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 987006 Hom.: 0 Cov.: 14 AF XY: 0.00 AC XY: 0 AN XY: 473054

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Paroxysmal nonkinesigenic dyskinesia Uncertain:1

May 22, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine with isoleucine at codon 16 of the PNKD protein (p.Arg16Ile). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and isoleucine. While this variant is not present in population databases, the frequency information is unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has not been reported in the literature in individuals with PNKD-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). 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 v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Uncertain	26
DANN	Uncertain	0.98
DEOGEN2	Benign	0.19	.;T
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Benign	0.34	N
LIST_S2	Uncertain	0.90	D;D
M_CAP	Benign	0.046	D
MetaRNN	Uncertain	0.48	T;T
MetaSVM	Uncertain	0.76	D
MutationAssessor	Benign	0.55	N;N
PrimateAI	Pathogenic	0.80	D
PROVEAN	Benign	-0.36	N;N
REVEL	Uncertain	0.38
Sift	Uncertain	0.013	D;D
Sift4G	Uncertain	0.042	D;T
Polyphen		0.99	D;P
Vest4		0.60
MutPred		0.30		Loss of disorder (P = 0.004);Loss of disorder (P = 0.004);
MVP		0.82
MPC		0.39
ClinPred		0.76	D
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.33
gMVP		0.39

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: rs1553654496; hg19: chr2-219135305; COSMIC: COSV50309812; COSMIC: COSV50309812;