rs34745867

chr2-218342015-C-Achr2-218342015-C-T

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.652C>A(p.Arg218=) 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:5
• Conservation: PhyloP100: 1.31

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

Verdict is Benign. Variant got -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 id 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 male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 26 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PNKD	NM_015488.5	c.652C>A	p.Arg218=	synonymous_variant	7/10	ENST00000273077.9
CATIP-AS2	NR_125777.1	n.120+9145G>T		intron_variant, non_coding_transcript_variant
MIR6810	NR_106868.1			downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PNKD	ENST00000273077.9	c.652C>A	p.Arg218=	synonymous_variant	7/10	1	NM_015488.5
CATIP-AS2	ENST00000411433.1	n.120+9145G>T		intron_variant, non_coding_transcript_variant		3
MIR6810	ENST00000622701.1			downstream_gene_variant

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

GnomAD3 exomes AF: 0.0159 AC: 4009 AN: 251396 Hom.: 62 AF XY: 0.0158 AC XY: 2141 AN XY: 135882

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 SAS exome AF: 0.00167

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

Gnomad4 AFR exome AF: 0.00350

Gnomad4 AMR exome AF: 0.00528

Gnomad4 ASJ exome AF: 0.00513

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00177

Gnomad4 FIN exome AF: 0.0272

Gnomad4 NFE exome AF: 0.0281

Gnomad4 OTH exome AF: 0.0194

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

Gnomad4 AFR AF: 0.00409

Gnomad4 AMR AF: 0.00961

Gnomad4 ASJ AF: 0.00634

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00166

Gnomad4 FIN AF: 0.0233

Gnomad4 NFE AF: 0.0287

Gnomad4 OTH AF: 0.0123

Alfa AF: 0.0198 Hom.: 32

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:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Paroxysmal nonkinesigenic dyskinesia 1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 09, 2017	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 11, 2018	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 29, 2016	- -

Paroxysmal nonkinesigenic dyskinesia Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.19
Cadd	Benign	11
Dann	Benign	0.82
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs34745867; hg19: chr2-219206738;