rs760050261

Positions:

• chr12-42460657-C-G
• chr12-42460657-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_153026.3(PRICKLE1):​c.1648G>C​(p.Val550Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000657 in 152,176 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: PRICKLE1 NM_153026.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.70

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]

(HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.18275759).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRICKLE1	NM_153026.3	c.1648G>C	p.Val550Leu	missense_variant	8/8	ENST00000345127.9	NP_694571.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRICKLE1	ENST00000345127.9	c.1648G>C	p.Val550Leu	missense_variant	8/8	1	NM_153026.3	ENSP00000345064	P1
	ENST00000547824.1	n.1292C>G		non_coding_transcript_exon_variant	1/2	1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152176 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 33

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152176 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74344

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.028	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Benign	0.081	T;T;T;T;T;T;T;T;T;T
Eigen	Benign	0.13
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.90	.;.;.;.;.;.;.;.;.;D
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.18	T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.1	L;L;L;L;L;L;L;L;L;L
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-0.92	N;.;N;.;N;.;.;N;.;N
REVEL	Benign	0.13
Sift	Benign	0.42	T;.;T;.;T;.;.;T;.;T
Sift4G	Benign	0.53	T;.;T;.;T;.;.;T;.;T
Polyphen		0.049	B;B;B;B;B;B;B;B;B;B
Vest4		0.14
MutPred		0.081		Loss of methylation at K555 (P = 0.0774);Loss of methylation at K555 (P = 0.0774);Loss of methylation at K555 (P = 0.0774);Loss of methylation at K555 (P = 0.0774);Loss of methylation at K555 (P = 0.0774);Loss of methylation at K555 (P = 0.0774);Loss of methylation at K555 (P = 0.0774);Loss of methylation at K555 (P = 0.0774);Loss of methylation at K555 (P = 0.0774);Loss of methylation at K555 (P = 0.0774);
MVP		0.42
MPC		0.38
ClinPred		0.55	D
GERP RS		5.6
Varity_R		0.22
gMVP		0.29

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: rs760050261; hg19: chr12-42854459;