rs34745867

Variant names:

• chr2-218342015-C-A
• rs34745867
• NM_015488.5:c.652C>A

Your query was ambiguous. Multiple possible variants found:

• chr2-218342015-C-A
• chr2-218342015-C-T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_015488.5(PNKD):​c.652C>A​(p.Arg218Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.023 in 1,613,408 control chromosomes in the GnomAD database, including 522 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.017 (26 hom., cov: 32)
  • Exomes 𝑓: 0.024 (496 hom.)
• Consequence: PNKD NM_015488.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.31
• Publications: 6 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)

MIR6810 (HGNC:49987): (microRNA 6810) microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.19).
• BP6: Variant 2-218342015-C-A is Benign according to our data. Variant chr2-218342015-C-A is described in ClinVar as Benign. ClinVar VariationId is 334323.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.31 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.017 (2583/152304) while in subpopulation NFE AF = 0.0287 (1953/68012). AF 95% confidence interval is 0.0277. There are 26 homozygotes in GnomAd4. There are 1165 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 2583 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PNKD	NM_015488.5	c.652C>A	p.Arg218Arg	synonymous_variant	Exon 7 of 10	ENST00000273077.9	NP_056303.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PNKD	ENST00000273077.9	c.652C>A	p.Arg218Arg	synonymous_variant	Exon 7 of 10	1	NM_015488.5	ENSP00000273077.4

Frequencies

GnomAD3 genomes AF: 0.0170 AC: 2583 AN: 152186 Hom.: 26 Cov.: 32

Gnomad AFR AF: 0.00410

Gnomad AMI AF: 0.00987

Gnomad AMR AF: 0.00963

Gnomad ASJ AF: 0.00634

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00165

Gnomad FIN AF: 0.0233

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0287

Gnomad OTH AF: 0.0124

GnomAD2 exomes AF: 0.0159 AC: 4009 AN: 251396 AF XY: 0.0158

Gnomad AFR exome AF: 0.00412

Gnomad AMR exome AF: 0.00480

Gnomad ASJ exome AF: 0.00486

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0242

Gnomad NFE exome AF: 0.0268

Gnomad OTH exome AF: 0.0173

GnomAD4 exome AF: 0.0237 AC: 34558 AN: 1461104 Hom.: 496 Cov.: 31 AF XY: 0.0232 AC XY: 16888 AN XY: 726918

African (AFR) AF: 0.00350 AC: 117 AN: 33472

American (AMR) AF: 0.00528 AC: 236 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00513 AC: 134 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39698

South Asian (SAS) AF: 0.00177 AC: 153 AN: 86250

European-Finnish (FIN) AF: 0.0272 AC: 1454 AN: 53418

Middle Eastern (MID) AF: 0.00399 AC: 23 AN: 5762

European-Non Finnish (NFE) AF: 0.0281 AC: 31271 AN: 1111274

Other (OTH) AF: 0.0194 AC: 1169 AN: 60370

GnomAD4 genome AF: 0.0170 AC: 2583 AN: 152304 Hom.: 26 Cov.: 32 AF XY: 0.0156 AC XY: 1165 AN XY: 74462

African (AFR) AF: 0.00409 AC: 170 AN: 41578

American (AMR) AF: 0.00961 AC: 147 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00634 AC: 22 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5182

South Asian (SAS) AF: 0.00166 AC: 8 AN: 4830

European-Finnish (FIN) AF: 0.0233 AC: 247 AN: 10618

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

European-Non Finnish (NFE) AF: 0.0287 AC: 1953 AN: 68012

Other (OTH) AF: 0.0123 AC: 26 AN: 2116

Alfa AF: 0.0207 Hom.: 39

Bravo AF: 0.0146

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.0237

EpiControl AF: 0.0228

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Feb 29, 2016

Mayo Clinic Laboratories, Mayo Clinic

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Dec 11, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Paroxysmal nonkinesigenic dyskinesia 1 Benign:2

Jun 09, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 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 02, 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	-0.19
CADD	Benign	11
DANN	Benign	0.82
PhyloP100		1.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism (auto)

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: rs34745867; hg19: chr2-219206738;