rs27673

chr3-64147674-A-Gchr3-64147674-A-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_198859.4(PRICKLE2):c.816T>C(p.Asp272=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.995 in 1,613,902 control chromosomes in the GnomAD database, including 799,631 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.99 (74145 hom., cov: 33)
  • Exomes 𝑓: 1.0 (725486 hom.)
• Consequence: PRICKLE2 NM_198859.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.979

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 3-64147674-A-G is Benign according to our data. Variant chr3-64147674-A-G is described in ClinVar as [Benign]. Clinvar id is 130137.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-64147674-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.979 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.991 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRICKLE2	NM_198859.4	c.816T>C	p.Asp272=	synonymous_variant	7/8	ENST00000638394.2
PRICKLE2	NM_001370528.1	c.816T>C	p.Asp272=	synonymous_variant	7/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRICKLE2	ENST00000638394.2	c.816T>C	p.Asp272=	synonymous_variant	7/8	1	NM_198859.4

Frequencies

GnomAD3 genomes AF: 0.986 AC: 150138 AN: 152202 Hom.: 74089 Cov.: 33

Gnomad AFR AF: 0.958

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.993

Gnomad ASJ AF: 1.00

Gnomad EAS AF: 1.00

Gnomad SAS AF: 1.00

Gnomad FIN AF: 0.999

Gnomad MID AF: 1.00

Gnomad NFE AF: 0.997

Gnomad OTH AF: 0.989

GnomAD3 exomes AF: 0.995 AC: 246851 AN: 248062 Hom.: 122840 AF XY: 0.996 AC XY: 133908 AN XY: 134434

Gnomad AFR exome AF: 0.954

Gnomad AMR exome AF: 0.995

Gnomad ASJ exome AF: 1.00

Gnomad EAS exome AF: 1.00

Gnomad SAS exome AF: 1.00

Gnomad FIN exome AF: 0.999

Gnomad NFE exome AF: 0.998

Gnomad OTH exome AF: 0.996

GnomAD4 exome AF: 0.996 AC: 1456230 AN: 1461582 Hom.: 725486 Cov.: 61 AF XY: 0.997 AC XY: 724608 AN XY: 727106

Gnomad4 AFR exome AF: 0.959

Gnomad4 AMR exome AF: 0.995

Gnomad4 ASJ exome AF: 1.00

Gnomad4 EAS exome AF: 1.00

Gnomad4 SAS exome AF: 1.00

Gnomad4 FIN exome AF: 0.999

Gnomad4 NFE exome AF: 0.997

Gnomad4 OTH exome AF: 0.994

GnomAD4 genome AF: 0.986 AC: 150253 AN: 152320 Hom.: 74145 Cov.: 33 AF XY: 0.987 AC XY: 73487 AN XY: 74480

Gnomad4 AFR AF: 0.958

Gnomad4 AMR AF: 0.993

Gnomad4 ASJ AF: 1.00

Gnomad4 EAS AF: 1.00

Gnomad4 SAS AF: 1.00

Gnomad4 FIN AF: 0.999

Gnomad4 NFE AF: 0.997

Gnomad4 OTH AF: 0.989

Alfa AF: 0.992 Hom.: 42986

Bravo AF: 0.985

Asia WGS AF: 0.998 AC: 3470 AN: 3478

EpiCase AF: 0.998

EpiControl AF: 0.998

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Progressive myoclonic epilepsy type 5 Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Nov 11, 2016	- -

not specified Benign:2

Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 20, 2018	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

May 03, 2018

- -

Progressive myoclonic epilepsy 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	-0.93
Cadd	Benign	0.025
Dann	Benign	0.27

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: rs27673; hg19: chr3-64133350;