2-218270551-G-C

Position:

• chr2-218270551-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_015488.5(PNKD):​c.16G>C​(p.Ala6Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A6T) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: PNKD NM_015488.5 missense
• Clinical Significance: Not reported in ClinVar
• 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 4 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 NM_015488.5
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PNKD	NM_015488.5	c.16G>C	p.Ala6Pro	missense_variant	1/10	ENST00000273077.9
PNKD	NM_001077399.3	c.16G>C	p.Ala6Pro	missense_variant	1/3
PNKD	XM_017003771.2	c.16G>C	p.Ala6Pro	missense_variant	1/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PNKD	ENST00000273077.9	c.16G>C	p.Ala6Pro	missense_variant	1/10	1	NM_015488.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 18

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.49
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.18
CADD	Pathogenic	30
DANN	Uncertain	1.0
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Benign	0.67	D
LIST_S2	Benign	0.81	T;T
M_CAP	Uncertain	0.11	D
MetaRNN	Uncertain	0.71	D;D
MetaSVM	Pathogenic	0.93	D
MutationAssessor	Benign	0.55	N;N
MutationTaster	Benign	0.77	D;D
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-0.86	N;N
REVEL	Uncertain	0.52
Sift	Uncertain	0.0090	D;D
Sift4G	Uncertain	0.047	D;D
Polyphen		1.0	D;D
Vest4		0.78
MutPred		0.41		Loss of sheet (P = 0.0181);Loss of sheet (P = 0.0181);
MVP		0.78
MPC		0.49
ClinPred		0.91	D
GERP RS		5.4
Varity_R		0.53
gMVP		0.54

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: rs1023163176; hg19: chr2-219135274;