2-218341922-A-G

Variant names:

• chr2-218341922-A-G
• rs62182086
• NM_015488.5:c.618-59A>G

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.618-59A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.126 in 1,382,778 control chromosomes in the GnomAD database, including 12,051 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (1056 hom., cov: 32)
  • Exomes 𝑓: 0.13 (10995 hom.)
• Consequence: PNKD NM_015488.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.741
• Publications: 13 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]

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]

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=-0.93).
• BP6: Variant 2-218341922-A-G is Benign according to our data. Variant chr2-218341922-A-G is described in ClinVar as [Benign]. Clinvar id is 1250259.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.14 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PNKD	NM_015488.5	c.618-59A>G		intron_variant	Intron 6 of 9	ENST00000273077.9	NP_056303.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PNKD	ENST00000273077.9	c.618-59A>G		intron_variant	Intron 6 of 9	1	NM_015488.5	ENSP00000273077.4

Frequencies

GnomAD3 genomes AF: 0.109 AC: 16560 AN: 152158 Hom.: 1057 Cov.: 32

Gnomad AFR AF: 0.0643

Gnomad AMI AF: 0.194

Gnomad AMR AF: 0.0671

Gnomad ASJ AF: 0.0833

Gnomad EAS AF: 0.0376

Gnomad SAS AF: 0.0665

Gnomad FIN AF: 0.185

Gnomad MID AF: 0.0854

Gnomad NFE AF: 0.143

Gnomad OTH AF: 0.0934

GnomAD2 exomes AF: 0.110 AC: 25482 AN: 232684 AF XY: 0.111

Gnomad AFR exome AF: 0.0670

Gnomad AMR exome AF: 0.0505

Gnomad ASJ exome AF: 0.0840

Gnomad EAS exome AF: 0.0483

Gnomad FIN exome AF: 0.184

Gnomad NFE exome AF: 0.142

Gnomad OTH exome AF: 0.111

GnomAD4 exome AF: 0.128 AC: 157688 AN: 1230502 Hom.: 10995 Cov.: 17 AF XY: 0.127 AC XY: 78813 AN XY: 622128

African (AFR) AF: 0.0645 AC: 1874 AN: 29056

American (AMR) AF: 0.0528 AC: 2248 AN: 42608

Ashkenazi Jewish (ASJ) AF: 0.0848 AC: 2082 AN: 24558

East Asian (EAS) AF: 0.0354 AC: 1360 AN: 38402

South Asian (SAS) AF: 0.0727 AC: 5861 AN: 80642

European-Finnish (FIN) AF: 0.177 AC: 9315 AN: 52756

Middle Eastern (MID) AF: 0.0934 AC: 458 AN: 4906

European-Non Finnish (NFE) AF: 0.142 AC: 128421 AN: 904716

Other (OTH) AF: 0.115 AC: 6069 AN: 52858

GnomAD4 genome AF: 0.109 AC: 16559 AN: 152276 Hom.: 1056 Cov.: 32 AF XY: 0.107 AC XY: 7997 AN XY: 74436

African (AFR) AF: 0.0642 AC: 2667 AN: 41572

American (AMR) AF: 0.0670 AC: 1026 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0833 AC: 289 AN: 3470

East Asian (EAS) AF: 0.0376 AC: 195 AN: 5180

South Asian (SAS) AF: 0.0663 AC: 320 AN: 4826

European-Finnish (FIN) AF: 0.185 AC: 1963 AN: 10602

Middle Eastern (MID) AF: 0.0850 AC: 25 AN: 294

European-Non Finnish (NFE) AF: 0.143 AC: 9701 AN: 68004

Other (OTH) AF: 0.0929 AC: 196 AN: 2110

Alfa AF: 0.124 Hom.: 240

Bravo AF: 0.0986

Asia WGS AF: 0.0470 AC: 165 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 05, 2018

GeneDx

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	-0.93
CADD	Benign	3.2
DANN	Benign	0.51
PhyloP100		-0.74
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: rs62182086; hg19: chr2-219206645; COSMIC: COSV51232824; COSMIC: COSV51232824;