2-218270551-G-A

Position:

• chr2-218270551-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1 PM2 BP4

The ENST00000273077.9(PNKD):​c.16G>A​(p.Ala6Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000566 in 1,236,758 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. A6S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000018 (0 hom.)
• Consequence: PNKD ENST00000273077.9 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 4.79

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 3 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain in ENST00000273077.9
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.4232082).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PNKD	NM_015488.5	c.16G>A	p.Ala6Thr	missense_variant	1/10	ENST00000273077.9	NP_056303.3
PNKD	NM_001077399.3	c.16G>A	p.Ala6Thr	missense_variant	1/3		NP_001070867.1
PNKD	XM_017003771.2	c.16G>A	p.Ala6Thr	missense_variant	1/9		XP_016859260.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PNKD	ENST00000273077.9	c.16G>A	p.Ala6Thr	missense_variant	1/10	1	NM_015488.5	ENSP00000273077

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152190 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000184 AC: 2 AN: 1084568 Hom.: 0 Cov.: 18 AF XY: 0.00000385 AC XY: 2 AN XY: 519898

Gnomad4 AFR exome AF: 0.0000437

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: 0.0000228

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152190 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74358

Gnomad4 AFR AF: 0.0000965

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000329 Hom.: 0

Bravo AF: 0.0000151

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	New York Genome Center	Jun 11, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Mar 19, 2020	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Paroxysmal nonkinesigenic dyskinesia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 22, 2023

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 6 of the PNKD protein (p.Ala6Thr). This variant is present in population databases (no rsID available, gnomAD 0.009%). This variant has not been reported in the literature in individuals affected with PNKD-related conditions. This missense change has been observed in at least one individual who was not affected with PNKD-related conditions (Invitae). ClinVar contains an entry for this variant (Variation ID: 536495). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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	0.35
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.17	.;T
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Benign	0.64	D
LIST_S2	Benign	0.83	T;T
M_CAP	Benign	0.067	D
MetaRNN	Benign	0.42	T;T
MetaSVM	Uncertain	0.77	D
MutationAssessor	Benign	0.55	N;N
MutationTaster	Benign	0.51	N;N
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-0.39	N;N
REVEL	Uncertain	0.41
Sift	Uncertain	0.0080	D;D
Sift4G	Benign	0.068	T;D
Polyphen		0.93	P;P
Vest4		0.61
MVP		0.86
MPC		0.32
ClinPred		0.93	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.33
gMVP		0.40

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1023163176; hg19: chr2-219135274;