12-42465080-G-C

Variant names:

• chr12-42465080-G-C
• rs139421676
• NM_153026.3:c.954C>G

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_153026.3(PRICKLE1):​c.954C>G​(p.Ser318Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000484 in 1,567,294 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. S318S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0027 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00025 (2 hom.)
• Consequence: PRICKLE1 NM_153026.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -4.52
• Publications: 2 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

ENSG00000257225 (HGNC:58444):

ACMG classification

Our verdict: Benign. The variant received -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 12-42465080-G-C is Benign according to our data. Variant chr12-42465080-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 138806.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-4.52 with no splicing effect.
• BS2: High Homozygotes in GnomAd4 at 2 AR,AD gene

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRICKLE1	NM_153026.3	MANE Select	c.954C>G	p.Ser318Ser	synonymous	Exon 7 of 8	NP_694571.2
	PRICKLE1	NM_001144881.2		c.954C>G	p.Ser318Ser	synonymous	Exon 7 of 8	NP_001138353.1
	PRICKLE1	NM_001144882.2		c.954C>G	p.Ser318Ser	synonymous	Exon 7 of 8	NP_001138354.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRICKLE1	ENST00000345127.9	TSL:1 MANE Select	c.954C>G	p.Ser318Ser	synonymous	Exon 7 of 8	ENSP00000345064.3
	ENSG00000257225	ENST00000547824.1	TSL:1	n.1743G>C		non_coding_transcript_exon	Exon 2 of 2
	PRICKLE1	ENST00000445766.7	TSL:5	c.954C>G	p.Ser318Ser	synonymous	Exon 7 of 8	ENSP00000398947.2

Frequencies

GnomAD3 genomes AF: 0.00267 AC: 406 AN: 152144 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00937

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000851

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: 0.00239

GnomAD2 exomes AF: 0.000786 AC: 164 AN: 208574 AF XY: 0.000594

Gnomad AFR exome AF: 0.00914

Gnomad AMR exome AF: 0.000593

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000101

Gnomad OTH exome AF: 0.000611

GnomAD4 exome AF: 0.000249 AC: 353 AN: 1415032 Hom.: 2 Cov.: 32 AF XY: 0.000229 AC XY: 160 AN XY: 699730

African (AFR) AF: 0.00922 AC: 293 AN: 31770

American (AMR) AF: 0.000597 AC: 22 AN: 36824

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22632

East Asian (EAS) AF: 0.00 AC: 0 AN: 39406

South Asian (SAS) AF: 0.00 AC: 0 AN: 76656

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51446

Middle Eastern (MID) AF: 0.000182 AC: 1 AN: 5508

European-Non Finnish (NFE) AF: 0.00000275 AC: 3 AN: 1092478

Other (OTH) AF: 0.000583 AC: 34 AN: 58312

GnomAD4 genome AF: 0.00267 AC: 406 AN: 152262 Hom.: 2 Cov.: 32 AF XY: 0.00262 AC XY: 195 AN XY: 74440

African (AFR) AF: 0.00934 AC: 388 AN: 41550

American (AMR) AF: 0.000850 AC: 13 AN: 15300

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4812

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68018

Other (OTH) AF: 0.00237 AC: 5 AN: 2112

Alfa AF: 0.000108 Hom.: 0

Bravo AF: 0.00291

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	not provided (2)
-	-	1	Epilepsy, progressive myoclonic, 1B (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.017
DANN	Benign	0.63
PhyloP100		-4.5

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: rs139421676; hg19: chr12-42858882;