rs121434511

Variant names:

• chr2-218270561-C-A
• rs121434511
• NM_015488.5:c.26C>A

Your query was ambiguous. Multiple possible variants found:

• chr2-218270561-C-A
• chr2-218270561-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PM5

The NM_015488.5(PNKD):​c.26C>A​(p.Ala9Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000187 in 1,067,808 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. A9V) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000019 (0 hom.)
• Consequence: PNKD NM_015488.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.51
• 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.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-218270561-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 1892.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PNKD	NM_015488.5	MANE Select	c.26C>A	p.Ala9Glu	missense	Exon 1 of 10	NP_056303.3
	PNKD	NM_001077399.3		c.26C>A	p.Ala9Glu	missense	Exon 1 of 3	NP_001070867.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PNKD	ENST00000273077.9	TSL:1 MANE Select	c.26C>A	p.Ala9Glu	missense	Exon 1 of 10	ENSP00000273077.4
	PNKD	ENST00000248451.7	TSL:1	c.26C>A	p.Ala9Glu	missense	Exon 1 of 3	ENSP00000248451.3
	PNKD	ENST00000685415.1		c.26C>A	p.Ala9Glu	missense	Exon 1 of 11	ENSP00000510415.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000187 AC: 2 AN: 1067808 Hom.: 0 Cov.: 18 AF XY: 0.00000391 AC XY: 2 AN XY: 511360

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 22650

American (AMR) AF: 0.00 AC: 0 AN: 12128

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14458

East Asian (EAS) AF: 0.00 AC: 0 AN: 27738

South Asian (SAS) AF: 0.00 AC: 0 AN: 27438

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38096

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4476

European-Non Finnish (NFE) AF: 0.00000114 AC: 1 AN: 877654

Other (OTH) AF: 0.0000232 AC: 1 AN: 43170

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.50
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.18	T
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Benign	0.44	N
LIST_S2	Benign	0.79	T
M_CAP	Uncertain	0.18	D
MetaRNN	Uncertain	0.63	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Benign	0.69	N
PhyloP100		1.5
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-1.0	N
REVEL	Uncertain	0.45
Sift	Uncertain	0.012	D
Sift4G	Uncertain	0.042	D
Polyphen		1.0	D
Vest4		0.73
MutPred		0.38		Gain of catalytic residue at A9 (P = 0.021)
MVP		0.83
MPC		0.50
ClinPred		0.97	D
GERP RS		5.4
PromoterAI		-0.0030	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.67
gMVP		0.72
Mutation Taster		=26/74	disease causing

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: rs121434511; hg19: chr2-219135284;