chr2-218344473-A-G

Variant names:

• chr2-218344473-A-G
• rs202211738
• NM_015488.5:c.887A>G

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP6 BS2

The NM_015488.5(PNKD):​c.887A>G​(p.Glu296Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000506 in 1,583,036 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00053 (12 hom.)
• Consequence: PNKD NM_015488.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 9.16
• 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]

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

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP6: Variant 2-218344473-A-G is Benign according to our data. Variant chr2-218344473-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 468636.
• BS2: High AC in GnomAd4 at 40 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.887A>G	p.Glu296Gly	missense	Exon 9 of 10	NP_056303.3
	PNKD	NM_022572.4		c.815A>G	p.Glu272Gly	missense	Exon 8 of 9	NP_072094.1
	CATIP-AS2	NR_125777.1		n.120+6687T>C		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PNKD	ENST00000273077.9	TSL:1 MANE Select	c.887A>G	p.Glu296Gly	missense	Exon 9 of 10	ENSP00000273077.4
	PNKD	ENST00000258362.7	TSL:1	c.815A>G	p.Glu272Gly	missense	Exon 8 of 9	ENSP00000258362.3
	PNKD	ENST00000685415.1		c.1004A>G	p.Glu335Gly	missense	Exon 10 of 11	ENSP00000510415.1

Frequencies

GnomAD3 genomes AF: 0.000256 AC: 39 AN: 152140 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00726

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00106 AC: 216 AN: 203562 AF XY: 0.00144

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000648

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000191

GnomAD4 exome AF: 0.000532 AC: 761 AN: 1430778 Hom.: 12 Cov.: 31 AF XY: 0.000756 AC XY: 536 AN XY: 708682

African (AFR) AF: 0.00 AC: 0 AN: 32990

American (AMR) AF: 0.00 AC: 0 AN: 39634

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25482

East Asian (EAS) AF: 0.00 AC: 0 AN: 38430

South Asian (SAS) AF: 0.00885 AC: 724 AN: 81806

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51278

Middle Eastern (MID) AF: 0.000873 AC: 5 AN: 5726

European-Non Finnish (NFE) AF: 9.12e-7 AC: 1 AN: 1096158

Other (OTH) AF: 0.000523 AC: 31 AN: 59274

GnomAD4 genome AF: 0.000263 AC: 40 AN: 152258 Hom.: 0 Cov.: 33 AF XY: 0.000484 AC XY: 36 AN XY: 74440

African (AFR) AF: 0.0000722 AC: 3 AN: 41568

American (AMR) AF: 0.00 AC: 0 AN: 15276

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

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5180

South Asian (SAS) AF: 0.00747 AC: 36 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68010

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000103 Hom.: 0

Bravo AF: 0.0000567

ExAC AF: 0.00107 AC: 129

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.42
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Uncertain	0.020
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.47	T
Eigen	Benign	0.14
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D
MetaRNN	Benign	0.012	T
MetaSVM	Uncertain	0.32	D
MutationAssessor	Benign	0.015	N
PhyloP100		9.2
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-3.2	D
REVEL	Uncertain	0.45
Sift	Benign	0.17	T
Sift4G	Benign	0.35	T
Polyphen		0.90	P
Vest4		0.53
MutPred		0.36		Loss of stability (P = 0.0585)
MVP		0.82
MPC		0.18
ClinPred		0.12	T
GERP RS		5.1
Varity_R		0.19
gMVP		0.57
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.33		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.33		Position offset: 18

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs202211738; hg19: chr2-219209196;