NM_015488.5:c.16G>T

Variant names:

• chr2-218270551-G-T
• rs1023163176
• NM_015488.5:c.16G>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM1 PM2 BP4

The NM_015488.5(PNKD):​c.16G>T​(p.Ala6Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000000922 in 1,084,568 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. A6T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 9.2e-7 (0 hom.)
• Consequence: PNKD NM_015488.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.79
• 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]

PNKD Gene-Disease associations (from GenCC):

• paroxysmal nonkinesigenic dyskinesia 1

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet
• Tourette syndrome

  Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 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, 12 uncertain in NM_015488.5
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3421514).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PNKD	NM_015488.5	MANE Select	c.16G>T	p.Ala6Ser	missense	Exon 1 of 10	NP_056303.3
	PNKD	NM_001077399.3		c.16G>T	p.Ala6Ser	missense	Exon 1 of 3	NP_001070867.1	Q8N490-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PNKD	ENST00000273077.9	TSL:1 MANE Select	c.16G>T	p.Ala6Ser	missense	Exon 1 of 10	ENSP00000273077.4	Q8N490-1
	PNKD	ENST00000248451.7	TSL:1	c.16G>T	p.Ala6Ser	missense	Exon 1 of 3	ENSP00000248451.3	Q8N490-2
	PNKD	ENST00000685415.1		c.16G>T	p.Ala6Ser	missense	Exon 1 of 11	ENSP00000510415.1	A0A8I5KXK0

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 9.22e-7 AC: 1 AN: 1084568 Hom.: 0 Cov.: 18 AF XY: 0.00000192 AC XY: 1 AN XY: 519898

African (AFR) AF: 0.00 AC: 0 AN: 22862

American (AMR) AF: 0.00 AC: 0 AN: 12414

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14664

East Asian (EAS) AF: 0.00 AC: 0 AN: 27890

South Asian (SAS) AF: 0.0000338 AC: 1 AN: 29568

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38520

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4492

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 890332

Other (OTH) AF: 0.00 AC: 0 AN: 43826

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.0
CADD	Uncertain	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.17	T
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Benign	0.66	D
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.059	D
MetaRNN	Benign	0.34	T
MetaSVM	Uncertain	0.63	D
MutationAssessor	Benign	0.55	N
PhyloP100		4.8
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-0.16	N
REVEL	Uncertain	0.30
Sift	Benign	0.24	T
Sift4G	Benign	0.34	T
Polyphen		0.96	D
Vest4		0.56
MutPred		0.35		Gain of glycosylation at A6 (P = 0.0135)
MVP		0.73
MPC		0.26
ClinPred		0.73	D
GERP RS		5.4
PromoterAI		-0.096	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.34
gMVP		0.34
Mutation Taster		=74/26	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: rs1023163176; hg19: chr2-219135274;