2-218344505-G-A

Variant names:

• chr2-218344505-G-A
• rs139825405
• NM_015488.5:c.919G>A

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_015488.5(PNKD):​c.919G>A​(p.Glu307Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00052 in 1,592,466 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00047 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00052 (1 hom.)
• Consequence: PNKD NM_015488.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 4.45
• Publications: 2 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]

CATIP-AS2 (HGNC:41079): (CATIP antisense RNA 2)

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.050423443).
• BP6: Variant 2-218344505-G-A is Benign according to our data. Variant chr2-218344505-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 536504.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 72 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PNKD	NM_015488.5	MANE Select	c.919G>A	p.Glu307Lys	missense	Exon 9 of 10	NP_056303.3
	PNKD	NM_022572.4		c.847G>A	p.Glu283Lys	missense	Exon 8 of 9	NP_072094.1
	CATIP-AS2	NR_125777.1		n.120+6655C>T		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PNKD	ENST00000273077.9	TSL:1 MANE Select	c.919G>A	p.Glu307Lys	missense	Exon 9 of 10	ENSP00000273077.4
	PNKD	ENST00000258362.7	TSL:1	c.847G>A	p.Glu283Lys	missense	Exon 8 of 9	ENSP00000258362.3
	PNKD	ENST00000685415.1		c.1036G>A	p.Glu346Lys	missense	Exon 10 of 11	ENSP00000510415.1

Frequencies

GnomAD3 genomes AF: 0.000473 AC: 72 AN: 152162 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000265

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000706

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000440 AC: 95 AN: 215808 AF XY: 0.000422

Gnomad AFR exome AF: 0.000153

Gnomad AMR exome AF: 0.0000329

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00139

Gnomad NFE exome AF: 0.000516

Gnomad OTH exome AF: 0.000543

GnomAD4 exome AF: 0.000525 AC: 756 AN: 1440304 Hom.: 1 Cov.: 31 AF XY: 0.000536 AC XY: 383 AN XY: 714304

African (AFR) AF: 0.000543 AC: 18 AN: 33152

American (AMR) AF: 0.0000972 AC: 4 AN: 41136

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25638

East Asian (EAS) AF: 0.00 AC: 0 AN: 38808

South Asian (SAS) AF: 0.000494 AC: 41 AN: 82992

European-Finnish (FIN) AF: 0.00150 AC: 78 AN: 51846

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5740

European-Non Finnish (NFE) AF: 0.000528 AC: 581 AN: 1101390

Other (OTH) AF: 0.000570 AC: 34 AN: 59602

GnomAD4 genome AF: 0.000473 AC: 72 AN: 152162 Hom.: 0 Cov.: 33 AF XY: 0.000471 AC XY: 35 AN XY: 74336

African (AFR) AF: 0.000265 AC: 11 AN: 41440

American (AMR) AF: 0.0000655 AC: 1 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4832

European-Finnish (FIN) AF: 0.000942 AC: 10 AN: 10618

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

European-Non Finnish (NFE) AF: 0.000706 AC: 48 AN: 68018

Other (OTH) AF: 0.000478 AC: 1 AN: 2090

Alfa AF: 0.000963 Hom.: 0

Bravo AF: 0.000317

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.000582 AC: 5

ExAC AF: 0.000429 AC: 52

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Uncertain	-0.020
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.20	T
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.88	D
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.050	T
MetaSVM	Uncertain	0.59	D
MutationAssessor	Benign	1.6	L
PhyloP100		4.5
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-1.7	N
REVEL	Uncertain	0.43
Sift	Benign	0.16	T
Sift4G	Benign	0.84	T
Polyphen		0.85	P
Vest4		0.44
MVP		0.83
MPC		0.21
ClinPred		0.030	T
GERP RS		5.1
Varity_R		0.15
gMVP		0.47
Mutation Taster		=81/19	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: rs139825405; hg19: chr2-219209228;