chr2-218270546-T-A

Variant names:

• chr2-218270546-T-A
• rs1574614822
• NM_015488.5:c.11T>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM1 PM2

The NM_015488.5(PNKD):​c.11T>A​(p.Val4Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000659 in 151,846 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. V4A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PNKD NM_015488.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.50
• 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 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, 12 uncertain in NM_015488.5
• PM2: Very rare variant in population databases, with high coverage

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.11T>A	p.Val4Glu	missense	Exon 1 of 10	NP_056303.3
	PNKD	NM_001077399.3		c.11T>A	p.Val4Glu	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.11T>A	p.Val4Glu	missense	Exon 1 of 10	ENSP00000273077.4	Q8N490-1
	PNKD	ENST00000248451.7	TSL:1	c.11T>A	p.Val4Glu	missense	Exon 1 of 3	ENSP00000248451.3	Q8N490-2
	PNKD	ENST00000685415.1		c.11T>A	p.Val4Glu	missense	Exon 1 of 11	ENSP00000510415.1	A0A8I5KXK0

Frequencies

GnomAD3 genomes AF: 0.00000659 AC: 1 AN: 151726 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

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 Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1076540 Hom.: 0 Cov.: 18 AF XY: 0.00 AC XY: 0 AN XY: 516198

African (AFR) AF: 0.00 AC: 0 AN: 22652

American (AMR) AF: 0.00 AC: 0 AN: 11986

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14620

East Asian (EAS) AF: 0.00 AC: 0 AN: 27626

South Asian (SAS) AF: 0.00 AC: 0 AN: 29572

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38456

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4400

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 883684

Other (OTH) AF: 0.00 AC: 0 AN: 43544

GnomAD4 genome AF: 0.00000659 AC: 1 AN: 151846 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74200

African (AFR) AF: 0.00 AC: 0 AN: 41394

American (AMR) AF: 0.00 AC: 0 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3458

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5168

South Asian (SAS) AF: 0.00 AC: 0 AN: 4802

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10556

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67866

Other (OTH) AF: 0.00 AC: 0 AN: 2102

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.45
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.040
CADD	Uncertain	25
DANN	Uncertain	0.97
DEOGEN2	Benign	0.19	T
Eigen	Benign	0.097
Eigen_PC	Benign	0.19
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.73	T
M_CAP	Uncertain	0.10	D
MetaRNN	Uncertain	0.65	D
MetaSVM	Uncertain	0.55	D
MutationAssessor	Benign	0.55	N
PhyloP100		1.5
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-0.55	N
REVEL	Uncertain	0.47
Sift	Benign	0.039	D
Sift4G	Benign	0.13	T
Polyphen		0.98	D
Vest4		0.75
MutPred		0.42		Loss of sheet (P = 3e-04)
MVP		0.81
MPC		0.41
ClinPred		0.67	D
GERP RS		3.0
PromoterAI		-0.039	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.0
Varity_R		0.54
gMVP		0.75
Mutation Taster		=65/35	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs1574614822; hg19: chr2-219135269;