rs9076

chr2-218346058-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_015488.5(PNKD):c.*1077G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.447 in 152,204 control chromosomes in the GnomAD database, including 17,051 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.45 (17030 hom., cov: 33)
  • Exomes 𝑓: 0.54 (21 hom.)
• Consequence: PNKD NM_015488.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.166

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 2-218346058-G-A is Benign according to our data. Variant chr2-218346058-G-A is described in ClinVar as [Benign]. Clinvar id is 334345.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.611 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PNKD	NM_015488.5	c.*1077G>A		3_prime_UTR_variant	10/10	ENST00000273077.9
CATIP-AS2	NR_125777.1	n.120+5102C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PNKD	ENST00000273077.9	c.*1077G>A		3_prime_UTR_variant	10/10	1	NM_015488.5
CATIP-AS2	ENST00000411433.1	n.120+5102C>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.447 AC: 67887 AN: 151924 Hom.: 17022 Cov.: 33

Gnomad AFR AF: 0.198

Gnomad AMI AF: 0.401

Gnomad AMR AF: 0.526

Gnomad ASJ AF: 0.473

Gnomad EAS AF: 0.629

Gnomad SAS AF: 0.587

Gnomad FIN AF: 0.597

Gnomad MID AF: 0.424

Gnomad NFE AF: 0.532

Gnomad OTH AF: 0.464

GnomAD4 exome AF: 0.544 AC: 87 AN: 160 Hom.: 21 Cov.: 0 AF XY: 0.523 AC XY: 46 AN XY: 88

Gnomad4 EAS exome AF: 0.558

Gnomad4 NFE exome AF: 0.450

Gnomad4 OTH exome AF: 0.500

GnomAD4 genome AF: 0.447 AC: 67904 AN: 152044 Hom.: 17030 Cov.: 33 AF XY: 0.453 AC XY: 33659 AN XY: 74342

Gnomad4 AFR AF: 0.198

Gnomad4 AMR AF: 0.526

Gnomad4 ASJ AF: 0.473

Gnomad4 EAS AF: 0.629

Gnomad4 SAS AF: 0.588

Gnomad4 FIN AF: 0.597

Gnomad4 NFE AF: 0.532

Gnomad4 OTH AF: 0.464

Alfa AF: 0.507 Hom.: 26113

Bravo AF: 0.427

Asia WGS AF: 0.620 AC: 2156 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Paroxysmal nonkinesigenic dyskinesia 1 Benign:1

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
Cadd	Benign	0.68
Dann	Benign	0.43
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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: rs9076; hg19: chr2-219210781; COSMIC: COSV51243078; COSMIC: COSV51243078;