rs34837068

Variant names:

• chr12-42469460-A-G
• rs34837068
• NM_153026.3:c.374T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_153026.3(PRICKLE1):​c.374T>C​(p.Val125Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00387 in 1,614,068 control chromosomes in the GnomAD database, including 225 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V125M) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.0075 (40 hom., cov: 32)
  • Exomes 𝑓: 0.0035 (185 hom.)
• Consequence: PRICKLE1 NM_153026.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 3.37
• Publications: 14 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0039996505).
• BP6: Variant 12-42469460-A-G is Benign according to our data. Variant chr12-42469460-A-G is described in ClinVar as Benign. ClinVar VariationId is 130028.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0985 is higher than 0.05.

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.374T>C	p.Val125Ala	missense	Exon 4 of 8	NP_694571.2	Q96MT3
	PRICKLE1	NM_001144881.2		c.374T>C	p.Val125Ala	missense	Exon 4 of 8	NP_001138353.1	Q96MT3
	PRICKLE1	NM_001144882.2		c.374T>C	p.Val125Ala	missense	Exon 4 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.374T>C	p.Val125Ala	missense	Exon 4 of 8	ENSP00000345064.3	Q96MT3
	PRICKLE1	ENST00000445766.7	TSL:5	c.374T>C	p.Val125Ala	missense	Exon 4 of 8	ENSP00000398947.2	Q96MT3
	PRICKLE1	ENST00000455697.6	TSL:5	c.374T>C	p.Val125Ala	missense	Exon 5 of 9	ENSP00000401060.1	Q96MT3

Frequencies

GnomAD3 genomes AF: 0.00750 AC: 1141 AN: 152116 Hom.: 39 Cov.: 32

Gnomad AFR AF: 0.00790

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0122

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.106

Gnomad SAS AF: 0.0104

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.00479

GnomAD2 exomes AF: 0.0112 AC: 2817 AN: 251386 AF XY: 0.00965

Gnomad AFR exome AF: 0.00763

Gnomad AMR exome AF: 0.0176

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.104

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000193

Gnomad OTH exome AF: 0.00652

GnomAD4 exome AF: 0.00349 AC: 5102 AN: 1461834 Hom.: 185 Cov.: 32 AF XY: 0.00329 AC XY: 2395 AN XY: 727222

African (AFR) AF: 0.00756 AC: 253 AN: 33480

American (AMR) AF: 0.0176 AC: 787 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0752 AC: 2985 AN: 39698

South Asian (SAS) AF: 0.00376 AC: 324 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53366

Middle Eastern (MID) AF: 0.00434 AC: 25 AN: 5764

European-Non Finnish (NFE) AF: 0.000173 AC: 192 AN: 1112012

Other (OTH) AF: 0.00887 AC: 536 AN: 60396

GnomAD4 genome AF: 0.00750 AC: 1141 AN: 152234 Hom.: 40 Cov.: 32 AF XY: 0.00775 AC XY: 577 AN XY: 74422

African (AFR) AF: 0.00790 AC: 328 AN: 41538

American (AMR) AF: 0.0122 AC: 186 AN: 15292

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

East Asian (EAS) AF: 0.106 AC: 548 AN: 5180

South Asian (SAS) AF: 0.0106 AC: 51 AN: 4812

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

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

European-Non Finnish (NFE) AF: 0.000265 AC: 18 AN: 68010

Other (OTH) AF: 0.00474 AC: 10 AN: 2110

Alfa AF: 0.00414 Hom.: 46

Bravo AF: 0.00893

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00931 AC: 41

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.0103 AC: 1245

Asia WGS AF: 0.0420 AC: 144 AN: 3478

EpiCase AF: 0.000709

EpiControl AF: 0.000296

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	1	Epilepsy, progressive myoclonic, 1B (1)
-	-	1	not provided (1)
-	-	1	PRICKLE1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.20	T
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.17
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Benign	0.42	T
MetaRNN	Benign	0.0040	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.45	N
PhyloP100		3.4
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.048
Sift	Benign	0.33	T
Sift4G	Benign	0.12	T
Polyphen		0.0010	B
Vest4		0.25
MPC		0.42
ClinPred		0.0099	T
GERP RS		4.3
Varity_R		0.046
gMVP		0.38
Mutation Taster		=100/0	polymorphism (auto)

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: rs34837068; hg19: chr12-42863262; COSMIC: COSV107440796; COSMIC: COSV107440796;