NM_015488.5:c.939G>A

Variant names:

• chr2-218344525-G-A
• rs116144189
• NM_015488.5:c.939G>A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_015488.5(PNKD):​c.939G>A​(p.Arg313Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.017 in 1,593,238 control chromosomes in the GnomAD database, including 287 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (22 hom., cov: 32)
  • Exomes 𝑓: 0.017 (265 hom.)
• Consequence: PNKD NM_015488.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 3.42

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

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.35).
• BP6: Variant 2-218344525-G-A is Benign according to our data. Variant chr2-218344525-G-A is described in ClinVar as [Benign]. Clinvar id is 334327.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-218344525-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=3.42 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0132 (2011/152312) while in subpopulation NFE AF= 0.0191 (1301/68022). AF 95% confidence interval is 0.0183. There are 22 homozygotes in gnomad4. There are 955 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 22 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PNKD	NM_015488.5	c.939G>A	p.Arg313Arg	synonymous_variant	Exon 9 of 10	ENST00000273077.9	NP_056303.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PNKD	ENST00000273077.9	c.939G>A	p.Arg313Arg	synonymous_variant	Exon 9 of 10	1	NM_015488.5	ENSP00000273077.4

Frequencies

GnomAD3 genomes AF: 0.0132 AC: 2011 AN: 152194 Hom.: 22 Cov.: 32

Gnomad AFR AF: 0.00401

Gnomad AMI AF: 0.0175

Gnomad AMR AF: 0.0134

Gnomad ASJ AF: 0.0262

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00496

Gnomad FIN AF: 0.0166

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0191

Gnomad OTH AF: 0.0124

GnomAD3 exomes AF: 0.0134 AC: 2868 AN: 213854 Hom.: 35 AF XY: 0.0135 AC XY: 1552 AN XY: 115136

Gnomad AFR exome AF: 0.00387

Gnomad AMR exome AF: 0.0110

Gnomad ASJ exome AF: 0.0244

Gnomad EAS exome AF: 0.000188

Gnomad SAS exome AF: 0.00505

Gnomad FIN exome AF: 0.0183

Gnomad NFE exome AF: 0.0179

Gnomad OTH exome AF: 0.0169

GnomAD4 exome AF: 0.0174 AC: 25093 AN: 1440926 Hom.: 265 Cov.: 31 AF XY: 0.0173 AC XY: 12358 AN XY: 714896

Gnomad4 AFR exome AF: 0.00275

Gnomad4 AMR exome AF: 0.0104

Gnomad4 ASJ exome AF: 0.0230

Gnomad4 EAS exome AF: 0.000103

Gnomad4 SAS exome AF: 0.00509

Gnomad4 FIN exome AF: 0.0174

Gnomad4 NFE exome AF: 0.0196

Gnomad4 OTH exome AF: 0.0163

GnomAD4 genome AF: 0.0132 AC: 2011 AN: 152312 Hom.: 22 Cov.: 32 AF XY: 0.0128 AC XY: 955 AN XY: 74474

Gnomad4 AFR AF: 0.00399

Gnomad4 AMR AF: 0.0134

Gnomad4 ASJ AF: 0.0262

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00497

Gnomad4 FIN AF: 0.0166

Gnomad4 NFE AF: 0.0191

Gnomad4 OTH AF: 0.0123

Alfa AF: 0.0163 Hom.: 9

Bravo AF: 0.0120

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Feb 25, 2016

Mayo Clinic Laboratories, Mayo Clinic

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 12, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 06, 2018

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Paroxysmal nonkinesigenic dyskinesia 1 Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Paroxysmal nonkinesigenic dyskinesia Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.35
CADD	Benign	14
DANN	Benign	0.86

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

Publications

LitVar

Other links and lift over

dbSNP: rs116144189; hg19: chr2-219209248;