chr12-42460208-G-T

Position:

• chr12-42460208-G-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_153026.3(PRICKLE1):​c.2097C>A​(p.Asp699Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PRICKLE1 NM_153026.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.424

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.03278464).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRICKLE1	NM_153026.3	c.2097C>A	p.Asp699Glu	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.2097C>A	p.Asp699Glu	missense_variant	8/8	1	NM_153026.3	ENSP00000345064	P1
	ENST00000547824.1	n.843G>T		non_coding_transcript_exon_variant	1/2	1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Epilepsy, progressive myoclonic, 1B Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Mar 24, 2017

Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The glutamic acid amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies. In summary, this variant is a novel missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a PRICKLE1-related disease. This sequence change replaces aspartic acid with glutamic acid at codon 699 of the PRICKLE1 protein (p.Asp699Glu). The aspartic acid residue is moderately conserved and there is a small physicochemical difference between aspartic acid and glutamic acid. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	15
DANN	Benign	0.87
DEOGEN2	Benign	0.026	T;T;T;T;T;T;T;T;T;T
Eigen	Benign	-0.84
Eigen_PC	Benign	-0.56
FATHMM_MKL	Benign	0.65	D
LIST_S2	Benign	0.57	.;.;.;.;.;.;.;.;.;T
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.033	T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	-1.2	N;N;N;N;N;N;N;N;N;N
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.41	T
PROVEAN	Benign	0.28	N;.;N;.;N;.;.;N;.;N
REVEL	Benign	0.21
Sift	Benign	1.0	T;.;T;.;T;.;.;T;.;T
Sift4G	Benign	1.0	T;.;T;.;T;.;.;T;.;T
Polyphen		0.0	B;B;B;B;B;B;B;B;B;B
Vest4		0.018
MutPred		0.20		Gain of glycosylation at P697 (P = 0.1099);Gain of glycosylation at P697 (P = 0.1099);Gain of glycosylation at P697 (P = 0.1099);Gain of glycosylation at P697 (P = 0.1099);Gain of glycosylation at P697 (P = 0.1099);Gain of glycosylation at P697 (P = 0.1099);Gain of glycosylation at P697 (P = 0.1099);Gain of glycosylation at P697 (P = 0.1099);Gain of glycosylation at P697 (P = 0.1099);Gain of glycosylation at P697 (P = 0.1099);
MVP		0.34
MPC		0.33
ClinPred		0.20	T
GERP RS		3.7
Varity_R		0.056
gMVP		0.14

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: rs1555229289; hg19: chr12-42854010;