3-64094994-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_198859.4(PRICKLE2):c.*4057G>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 0.00334 in 152,296 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0033 (6 hom., cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PRICKLE2 NM_198859.4 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.63

Genes affected

PRICKLE2 (HGNC:20340): (prickle planar cell polarity protein 2) This gene encodes a homolog of Drosophila prickle. The exact function of this gene is not known, however, studies in mice suggest that it may be involved in seizure prevention. Mutations in this gene are associated with progressive myoclonic epilepsy type 5. [provided by RefSeq, Dec 2011]

PRICKLE2-AS1 (HGNC:40916): (PRICKLE2 antisense RNA 1)

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 3-64094994-C-T is Benign according to our data. Variant chr3-64094994-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 346425.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00334 (509/152296) while in subpopulation SAS AF= 0.0215 (104/4830). AF 95% confidence interval is 0.0182. There are 6 homozygotes in gnomad4. There are 258 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd at 510 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRICKLE2	NM_198859.4	c.*4057G>A		3_prime_UTR_variant	8/8	ENST00000638394.2
PRICKLE2-AS1	NR_045697.1	n.199-100C>T		intron_variant, non_coding_transcript_variant
PRICKLE2	NM_001370528.1	c.*4057G>A		3_prime_UTR_variant	8/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRICKLE2	ENST00000638394.2	c.*4057G>A		3_prime_UTR_variant	8/8	1	NM_198859.4
PRICKLE2-AS1	ENST00000482609.1	n.199-100C>T		intron_variant, non_coding_transcript_variant		1
PRICKLE2	ENST00000295902.11	c.*4057G>A		3_prime_UTR_variant	9/9	5		P1
PRICKLE2	ENST00000564377.6	c.*4057G>A		3_prime_UTR_variant	8/8	5

Frequencies

GnomAD3 genomes AF: 0.00335 AC: 510 AN: 152178 Hom.: 6 Cov.: 33

Gnomad AFR AF: 0.000265

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00301

Gnomad ASJ AF: 0.0401

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0215

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.00278

Gnomad OTH AF: 0.00525

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 432 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 260

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00334 AC: 509 AN: 152296 Hom.: 6 Cov.: 33 AF XY: 0.00346 AC XY: 258 AN XY: 74480

Gnomad4 AFR AF: 0.000265

Gnomad4 AMR AF: 0.00301

Gnomad4 ASJ AF: 0.0401

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0215

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.00278

Gnomad4 OTH AF: 0.00520

Alfa AF: 0.000366 Hom.: 0

Bravo AF: 0.00315

Asia WGS AF: 0.00866 AC: 30 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Progressive myoclonic epilepsy Benign:1

Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
Cadd	Benign	0.13
Dann	Benign	0.45

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: rs140931283; hg19: chr3-64080670;