12-42460417-G-T

Position:

• chr12-42460417-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_153026.3(PRICKLE1):​c.1888C>A​(p.Gln630Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts 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: 8.88

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3926028).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRICKLE1	NM_153026.3	c.1888C>A	p.Gln630Lys	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.1888C>A	p.Gln630Lys	missense_variant	8/8	1	NM_153026.3	ENSP00000345064	P1
	ENST00000547824.1	n.1052G>T		non_coding_transcript_exon_variant	1/2	1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 25, 2020

The p.Q630K variant (also known as c.1888C>A), located in coding exon 7 of the PRICKLE1 gene, results from a C to A substitution at nucleotide position 1888. The glutamine at codon 630 is replaced by lysine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.060
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.18	T;T;T;T;T;T;T;T;T;T
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.94	.;.;.;.;.;.;.;.;.;D
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.39	T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.65	T
MutationAssessor	Uncertain	2.1	M;M;M;M;M;M;M;M;M;M
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-1.1	N;.;N;.;N;.;.;N;.;N
REVEL	Benign	0.20
Sift	Benign	0.035	D;.;D;.;D;.;.;D;.;D
Sift4G	Benign	0.56	T;.;T;.;T;.;.;T;.;T
Polyphen		0.86	P;P;P;P;P;P;P;P;P;P
Vest4		0.63
MutPred		0.35		Gain of methylation at Q630 (P = 0.0013);Gain of methylation at Q630 (P = 0.0013);Gain of methylation at Q630 (P = 0.0013);Gain of methylation at Q630 (P = 0.0013);Gain of methylation at Q630 (P = 0.0013);Gain of methylation at Q630 (P = 0.0013);Gain of methylation at Q630 (P = 0.0013);Gain of methylation at Q630 (P = 0.0013);Gain of methylation at Q630 (P = 0.0013);Gain of methylation at Q630 (P = 0.0013);
MVP		0.36
MPC		0.96
ClinPred		0.92	D
GERP RS		5.1
Varity_R		0.32
gMVP		0.50

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: rs200171609; hg19: chr12-42854219;