rs9076

Variant names:

• chr2-218346058-G-A
• rs9076
• NM_015488.5:c.*1077G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong 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, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.166
• Publications: 21 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)

ACMG classification

Our verdict: Benign. The variant received -20 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 VariationId is 334345.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.611 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015488.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PNKD	NM_015488.5	MANE Select	c.*1077G>A		3_prime_UTR	Exon 10 of 10	NP_056303.3
	PNKD	NM_022572.4		c.*1077G>A		3_prime_UTR	Exon 9 of 9	NP_072094.1
	CATIP-AS2	NR_125777.1		n.120+5102C>T		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PNKD	ENST00000273077.9	TSL:1 MANE Select	c.*1077G>A		3_prime_UTR	Exon 10 of 10	ENSP00000273077.4
	PNKD	ENST00000258362.7	TSL:1	c.*1077G>A		3_prime_UTR	Exon 9 of 9	ENSP00000258362.3
	PNKD	ENST00000684905.1		n.2993G>A		non_coding_transcript_exon	Exon 9 of 9

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

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AF: 0.558 AC: 77 AN: 138

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.450 AC: 9 AN: 20

Other (OTH) AF: 0.500 AC: 1 AN: 2

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

African (AFR) AF: 0.198 AC: 8213 AN: 41482

American (AMR) AF: 0.526 AC: 8037 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.473 AC: 1642 AN: 3470

East Asian (EAS) AF: 0.629 AC: 3244 AN: 5160

South Asian (SAS) AF: 0.588 AC: 2837 AN: 4826

European-Finnish (FIN) AF: 0.597 AC: 6304 AN: 10562

Middle Eastern (MID) AF: 0.435 AC: 128 AN: 294

European-Non Finnish (NFE) AF: 0.532 AC: 36152 AN: 67952

Other (OTH) AF: 0.464 AC: 981 AN: 2112

Alfa AF: 0.502 Hom.: 69589

Bravo AF: 0.427

Asia WGS AF: 0.620 AC: 2156 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Paroxysmal nonkinesigenic dyskinesia 1 Benign:1

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.

not provided Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.68
DANN	Benign	0.43
PhyloP100		0.17
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
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: rs9076; hg19: chr2-219210781; COSMIC: COSV51243078; COSMIC: COSV51243078;