rs35731866

Variant names:

• chr12-42468823-A-C
• rs35731866
• NM_153026.3:c.391T>G

Your query was ambiguous. Multiple possible variants found:

• chr12-42468823-A-C
• chr12-42468823-A-G

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_153026.3(PRICKLE1):​c.391T>G​(p.Leu131Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00027 in 1,614,116 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict 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. L131L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00028 (4 hom.)
• Consequence: PRICKLE1 NM_153026.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:8
• Conservation: PhyloP100: 0.122
• Publications: 4 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

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.01460582).
• BS2: High Homozygotes in GnomAdExome4 at 4 AR,AD gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRICKLE1	NM_153026.3	MANE Select	c.391T>G	p.Leu131Val	missense	Exon 5 of 8	NP_694571.2	Q96MT3
	PRICKLE1	NM_001144881.2		c.391T>G	p.Leu131Val	missense	Exon 5 of 8	NP_001138353.1	Q96MT3
	PRICKLE1	NM_001144882.2		c.391T>G	p.Leu131Val	missense	Exon 5 of 8	NP_001138354.1	Q96MT3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRICKLE1	ENST00000345127.9	TSL:1 MANE Select	c.391T>G	p.Leu131Val	missense	Exon 5 of 8	ENSP00000345064.3	Q96MT3
	PRICKLE1	ENST00000445766.7	TSL:5	c.391T>G	p.Leu131Val	missense	Exon 5 of 8	ENSP00000398947.2	Q96MT3
	PRICKLE1	ENST00000455697.6	TSL:5	c.391T>G	p.Leu131Val	missense	Exon 6 of 9	ENSP00000401060.1	Q96MT3

Frequencies

GnomAD3 genomes AF: 0.000138 AC: 21 AN: 152212 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000351 AC: 88 AN: 250824 AF XY: 0.000435

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.000174

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000463

Gnomad NFE exome AF: 0.000344

Gnomad OTH exome AF: 0.000817

GnomAD4 exome AF: 0.000285 AC: 416 AN: 1461786 Hom.: 4 Cov.: 33 AF XY: 0.000345 AC XY: 251 AN XY: 727192

African (AFR) AF: 0.000179 AC: 6 AN: 33480

American (AMR) AF: 0.000201 AC: 9 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00158 AC: 136 AN: 86254

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53392

Middle Eastern (MID) AF: 0.00295 AC: 17 AN: 5768

European-Non Finnish (NFE) AF: 0.000208 AC: 231 AN: 1111946

Other (OTH) AF: 0.000265 AC: 16 AN: 60390

GnomAD4 genome AF: 0.000131 AC: 20 AN: 152330 Hom.: 0 Cov.: 32 AF XY: 0.000148 AC XY: 11 AN XY: 74486

African (AFR) AF: 0.00 AC: 0 AN: 41578

American (AMR) AF: 0.0000654 AC: 1 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000206 AC: 14 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.000133 Hom.: 0

Bravo AF: 0.000140

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000354 AC: 43

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.000654

EpiControl AF: 0.000830

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	4	-	Epilepsy, progressive myoclonic, 1B (4)
-	2	-	not provided (2)
-	1	-	not specified (1)
-	1	-	PRICKLE1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	0.83
DANN	Benign	0.72
DEOGEN2	Benign	0.20	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.68	T
M_CAP	Benign	0.043	D
MetaRNN	Benign	0.015	T
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	1.1	L
PhyloP100		0.12
PrimateAI	Benign	0.32	T
PROVEAN	Benign	0.54	N
REVEL	Benign	0.20
Sift	Benign	0.20	T
Sift4G	Benign	0.43	T
Polyphen		0.0020	B
Vest4		0.28
MVP		0.57
MPC		0.37
ClinPred		0.018	T
GERP RS		-10
Varity_R		0.023
gMVP		0.18
Mutation Taster		=99/1	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: rs35731866; hg19: chr12-42862625;