rs138524511

chr12-42459866-C-Achr12-42459866-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.2439G>T(p.Arg813Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000658 in 152,056 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. R813R) has been classified as Likely benign.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: PRICKLE1 NM_153026.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.61

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=0.22058904).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRICKLE1	NM_153026.3	c.2439G>T	p.Arg813Ser	missense_variant	8/8	ENST00000345127.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRICKLE1	ENST00000345127.9	c.2439G>T	p.Arg813Ser	missense_variant	8/8	1	NM_153026.3	P1
	ENST00000547824.1	n.501C>A		non_coding_transcript_exon_variant	1/2	1

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152056 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 33

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152056 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74250

Gnomad4 AFR AF: 0.00

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: 0.0000147

Gnomad4 OTH AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
Cadd	Benign	20
Dann	Uncertain	0.99
DEOGEN2	Benign	0.059	T;T;T;T;T;T;T;T;T;T
Eigen	Uncertain	0.25
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Uncertain	0.97	D
M_CAP	Benign	0.038	D
MetaRNN	Benign	0.22	T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.75	T
MutationAssessor	Benign	1.7	L;L;L;L;L;L;L;L;L;L
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-1.3	N;.;N;.;N;.;.;N;.;N
REVEL	Benign	0.20
Sift	Uncertain	0.0070	D;.;D;.;D;.;.;D;.;D
Sift4G	Benign	0.13	T;.;T;.;T;.;.;T;.;T
Polyphen		0.65	P;P;P;P;P;P;P;P;P;P
Vest4		0.31
MutPred		0.23		Loss of catalytic residue at R813 (P = 0.0103);Loss of catalytic residue at R813 (P = 0.0103);Loss of catalytic residue at R813 (P = 0.0103);Loss of catalytic residue at R813 (P = 0.0103);Loss of catalytic residue at R813 (P = 0.0103);Loss of catalytic residue at R813 (P = 0.0103);Loss of catalytic residue at R813 (P = 0.0103);Loss of catalytic residue at R813 (P = 0.0103);Loss of catalytic residue at R813 (P = 0.0103);Loss of catalytic residue at R813 (P = 0.0103);
MVP		0.53
MPC		0.59
ClinPred		0.78	D
GERP RS		4.7
Varity_R		0.51
gMVP		0.47

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: rs138524511; hg19: chr12-42853668; COSMIC: COSV104616769; COSMIC: COSV104616769;