rs34014804

chr2-218340748-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_015488.5(PNKD):c.486G>A(p.Gly162=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0449 in 1,613,360 control chromosomes in the GnomAD database, including 1,975 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.062 (349 hom., cov: 32)
  • Exomes 𝑓: 0.043 (1626 hom.)
• Consequence: PNKD NM_015488.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -2.49

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 2-218340748-G-A is Benign according to our data. Variant chr2-218340748-G-A is described in ClinVar as [Benign]. Clinvar id is 260662.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-218340748-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-2.49 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.103 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PNKD	NM_015488.5	c.486G>A	p.Gly162=	synonymous_variant	5/10	ENST00000273077.9
CATIP-AS2	NR_125777.1	n.120+10412C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PNKD	ENST00000273077.9	c.486G>A	p.Gly162=	synonymous_variant	5/10	1	NM_015488.5
CATIP-AS2	ENST00000411433.1	n.120+10412C>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.0619 AC: 9405 AN: 152008 Hom.: 348 Cov.: 32

Gnomad AFR AF: 0.105

Gnomad AMI AF: 0.0848

Gnomad AMR AF: 0.0508

Gnomad ASJ AF: 0.0922

Gnomad EAS AF: 0.00310

Gnomad SAS AF: 0.0237

Gnomad FIN AF: 0.0374

Gnomad MID AF: 0.0538

Gnomad NFE AF: 0.0470

Gnomad OTH AF: 0.0618

GnomAD3 exomes AF: 0.0432 AC: 10863 AN: 251456 Hom.: 301 AF XY: 0.0426 AC XY: 5791 AN XY: 135908

Gnomad AFR exome AF: 0.104

Gnomad AMR exome AF: 0.0344

Gnomad ASJ exome AF: 0.0888

Gnomad EAS exome AF: 0.00234

Gnomad SAS exome AF: 0.0241

Gnomad FIN exome AF: 0.0343

Gnomad NFE exome AF: 0.0463

Gnomad OTH exome AF: 0.0493

GnomAD4 exome AF: 0.0431 AC: 63009 AN: 1461234 Hom.: 1626 Cov.: 31 AF XY: 0.0430 AC XY: 31248 AN XY: 726932

Gnomad4 AFR exome AF: 0.103

Gnomad4 AMR exome AF: 0.0369

Gnomad4 ASJ exome AF: 0.0881

Gnomad4 EAS exome AF: 0.00131

Gnomad4 SAS exome AF: 0.0240

Gnomad4 FIN exome AF: 0.0322

Gnomad4 NFE exome AF: 0.0438

Gnomad4 OTH exome AF: 0.0450

GnomAD4 genome AF: 0.0619 AC: 9416 AN: 152126 Hom.: 349 Cov.: 32 AF XY: 0.0605 AC XY: 4496 AN XY: 74366

Gnomad4 AFR AF: 0.105

Gnomad4 AMR AF: 0.0508

Gnomad4 ASJ AF: 0.0922

Gnomad4 EAS AF: 0.00310

Gnomad4 SAS AF: 0.0241

Gnomad4 FIN AF: 0.0374

Gnomad4 NFE AF: 0.0470

Gnomad4 OTH AF: 0.0607

Alfa AF: 0.0556 Hom.: 128

Bravo AF: 0.0649

Asia WGS AF: 0.0270 AC: 94 AN: 3478

EpiCase AF: 0.0552

EpiControl AF: 0.0560

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Paroxysmal nonkinesigenic dyskinesia 1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 09, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 11, 2018	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 25, 2016	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

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	-0.84
Cadd	Benign	4.5
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)		0.060		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: rs34014804; hg19: chr2-219205471;