2-218270431-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000248451.7(PNKD):c.-105A>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0022 in 599,748 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0065 (9 hom., cov: 33)
  • Exomes 𝑓: 0.00075 (4 hom.)
• Consequence: PNKD ENST00000248451.7 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -3.35

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.66).
• BP6: Variant 2-218270431-A-T is Benign according to our data. Variant chr2-218270431-A-T is described in ClinVar as [Likely_benign]. Clinvar id is 334304.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00646 (983/152234) while in subpopulation AFR AF= 0.0223 (925/41548). AF 95% confidence interval is 0.0211. There are 9 homozygotes in gnomad4. There are 478 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PNKD	ENST00000248451.7	c.-105A>T		5_prime_UTR_variant	1/3	1
PNKD	ENST00000691799.1	n.70+711A>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.00646 AC: 983 AN: 152116 Hom.: 9 Cov.: 33

Gnomad AFR AF: 0.0223

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00203

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.00431

GnomAD4 exome AF: 0.000749 AC: 335 AN: 447514 Hom.: 4 Cov.: 6 AF XY: 0.000656 AC XY: 152 AN XY: 231656

Gnomad4 AFR exome AF: 0.0224

Gnomad4 AMR exome AF: 0.000659

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000599

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000162

Gnomad4 OTH exome AF: 0.00136

GnomAD4 genome AF: 0.00646 AC: 983 AN: 152234 Hom.: 9 Cov.: 33 AF XY: 0.00642 AC XY: 478 AN XY: 74430

Gnomad4 AFR AF: 0.0223

Gnomad4 AMR AF: 0.00203

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000265

Gnomad4 OTH AF: 0.00426

Alfa AF: 0.00569 Hom.: 1

Bravo AF: 0.00758

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Paroxysmal nonkinesigenic dyskinesia 1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Dec 24, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
Cadd	Benign	0.31
Dann	Benign	0.82

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs183319984; hg19: chr2-219135154;