rs763169354

Variant names:

• chr12-42464413-C-A
• rs763169354
• NM_153026.3:c.1621G>T

Your query was ambiguous. Multiple possible variants found:

• chr12-42464413-C-A
• chr12-42464413-C-T

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP4

The NM_153026.3(PRICKLE1):​c.1621G>T​(p.Ala541Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000219 in 1,461,894 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. A541A) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000022 (0 hom.)
• Consequence: PRICKLE1 NM_153026.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.85
• Publications: 2 publications found

Genes affected

PRICKLE1 (HGNC:17019): (prickle planar cell polarity protein 1) This gene encodes a nuclear receptor that may be a negative regulator of the Wnt/beta-catenin signaling pathway. The encoded protein localizes to the nuclear membrane and has been implicated in the nuclear trafficking of the transcription repressors REST/NRSF and REST4. Mutations in this gene have been linked to progressive myoclonus epilepsy. Alternate splicing results in multiple transcript variants. A pseudogene of this gene is found on chromosome 3. [provided by RefSeq, Sep 2009]

PRICKLE1 Gene-Disease associations (from GenCC):

• epilepsy, progressive myoclonic, 1B

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• Unverricht-Lundborg syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• progressive myoclonus epilepsy

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen
• epilepsy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ENSG00000257225 (HGNC:58444):

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.28370535).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_153026.3. 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
	PRICKLE1	NM_153026.3	MANE Select	c.1621G>T	p.Ala541Ser	missense	Exon 7 of 8	NP_694571.2
	PRICKLE1	NM_001144881.2		c.1621G>T	p.Ala541Ser	missense	Exon 7 of 8	NP_001138353.1
	PRICKLE1	NM_001144882.2		c.1621G>T	p.Ala541Ser	missense	Exon 7 of 8	NP_001138354.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRICKLE1	ENST00000345127.9	TSL:1 MANE Select	c.1621G>T	p.Ala541Ser	missense	Exon 7 of 8	ENSP00000345064.3
	ENSG00000257225	ENST00000547824.1	TSL:1	n.1364-288C>A		intron	N/A
	PRICKLE1	ENST00000445766.7	TSL:5	c.1621G>T	p.Ala541Ser	missense	Exon 7 of 8	ENSP00000398947.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000278 AC: 7 AN: 251446 AF XY: 0.0000147

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000326

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000219 AC: 32 AN: 1461894 Hom.: 0 Cov.: 32 AF XY: 0.0000248 AC XY: 18 AN XY: 727248

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.000756 AC: 30 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112012

Other (OTH) AF: 0.0000331 AC: 2 AN: 60396

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.0000165 AC: 2

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Epilepsy, progressive myoclonic, 1B (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.40
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.17
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.30	T
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.039	D
MetaRNN	Benign	0.28	T
MetaSVM	Benign	-0.39	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		5.8
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-0.77	N
REVEL	Benign	0.17
Sift	Uncertain	0.027	D
Sift4G	Benign	0.30	T
Polyphen		0.93	P
Vest4		0.53
MutPred		0.14		Gain of phosphorylation at A541 (P = 0.0337)
MVP		0.55
MPC		0.68
ClinPred		0.17	T
GERP RS		4.6
Varity_R		0.29
gMVP		0.50
Mutation Taster		=79/21	polymorphism

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: rs763169354; hg19: chr12-42858215;