rs1023163176

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr2-218270551-G-A
• chr2-218270551-G-C
• chr2-218270551-G-T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM1 BP4 BS2

The NM_015488.5(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 NM_015488.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• 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: Likely_benign. 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
• BP4: Computational evidence support a benign effect (MetaRNN=0.4232082).
• BS2: High AC in GnomAd4 at 5 AD gene.

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>A	p.Ala6Thr	missense	Exon 1 of 10	NP_056303.3
	PNKD	NM_001077399.3		c.16G>A	p.Ala6Thr	missense	Exon 1 of 3	NP_001070867.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PNKD	ENST00000273077.9	TSL:1 MANE Select	c.16G>A	p.Ala6Thr	missense	Exon 1 of 10	ENSP00000273077.4
	PNKD	ENST00000248451.7	TSL:1	c.16G>A	p.Ala6Thr	missense	Exon 1 of 3	ENSP00000248451.3
	PNKD	ENST00000685415.1		c.16G>A	p.Ala6Thr	missense	Exon 1 of 11	ENSP00000510415.1

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

GnomAD2 exomes AF: 0.00 AC: 0 AN: 49208 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome 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

African (AFR) AF: 0.0000437 AC: 1 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: 0.00 AC: 0 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: 0.0000228 AC: 1 AN: 43826

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

African (AFR) AF: 0.0000965 AC: 4 AN: 41462

American (AMR) AF: 0.00 AC: 0 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68014

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.0000329 Hom.: 0

Bravo AF: 0.0000151

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	not provided (2)
-	1	-	Paroxysmal nonkinesigenic dyskinesia (1)

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Benign	0.067	D
MetaRNN	Benign	0.42	T
MetaSVM	Uncertain	0.77	D
MutationAssessor	Benign	0.55	N
PhyloP100		4.8
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-0.39	N
REVEL	Uncertain	0.41
Sift	Uncertain	0.0080	D
Sift4G	Benign	0.068	T
Polyphen		0.93	P
Vest4		0.61
MVP		0.86
MPC		0.32
ClinPred		0.93	D
GERP RS		5.4
PromoterAI		-0.12	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.33
gMVP		0.40
Mutation Taster		=66/34	polymorphism

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

Other links and lift over

dbSNP: rs1023163176; hg19: chr2-219135274;