2-218270537-T-G

Variant names:

• chr2-218270537-T-G
• rs775653461
• NM_015488.5:c.2T>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PVS1_Moderate BS2

The NM_015488.5(PNKD):​c.2T>G​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000743 in 1,076,938 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000074 (0 hom.)
• Consequence: PNKD NM_015488.5 start_lost
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.45
• 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 -2 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 2 pathogenic variants. Next in-frame start position is after 72 codons. Genomic position: 218271527. Lost 0.185 part of the original CDS.
• BS2: High AC in GnomAdExome4 at 8 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.2T>G	p.Met1?	start_lost	Exon 1 of 10	NP_056303.3
	PNKD	NM_001077399.3		c.2T>G	p.Met1?	start_lost	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.2T>G	p.Met1?	start_lost	Exon 1 of 10	ENSP00000273077.4	Q8N490-1
	PNKD	ENST00000248451.7	TSL:1	c.2T>G	p.Met1?	start_lost	Exon 1 of 3	ENSP00000248451.3	Q8N490-2
	PNKD	ENST00000685415.1		c.2T>G	p.Met1?	start_lost	Exon 1 of 11	ENSP00000510415.1	A0A8I5KXK0

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00 AC: 0 AN: 51616 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: 0.00000743 AC: 8 AN: 1076938 Hom.: 0 Cov.: 17 AF XY: 0.00000386 AC XY: 2 AN XY: 517730

African (AFR) AF: 0.00 AC: 0 AN: 22696

American (AMR) AF: 0.00 AC: 0 AN: 12464

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14706

East Asian (EAS) AF: 0.00 AC: 0 AN: 27950

South Asian (SAS) AF: 0.00 AC: 0 AN: 31180

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39146

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4448

European-Non Finnish (NFE) AF: 0.00000908 AC: 8 AN: 880762

Other (OTH) AF: 0.00 AC: 0 AN: 43586

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000909 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.67
CADD	Uncertain	25
DANN	Uncertain	0.98
DEOGEN2	Benign	0.18	T
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Benign	0.48	N
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.91	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
PhyloP100		2.4
PROVEAN	Benign	-0.68	N
REVEL	Pathogenic	0.73
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0080	D
Polyphen		0.99	D
Vest4		0.85
MutPred		0.96		Gain of methylation at M1 (P = 0.0075)
MVP		0.87
ClinPred		0.99	D
GERP RS		5.4
PromoterAI		-0.82	Under-expression
Varity_R		0.98
gMVP		0.80
Mutation Taster		=45/155	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: rs775653461; hg19: chr2-219135260;