12-42460089-G-C

Variant names:

• chr12-42460089-G-C
• NM_153026.3:c.2216C>G

Variant summary

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

The NM_153026.3(PRICKLE1):​c.2216C>G​(p.Ser739Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,878 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S739F) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PRICKLE1 NM_153026.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.15

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]

ENSG00000257225 (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=0.37306213).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRICKLE1	NM_153026.3	c.2216C>G	p.Ser739Cys	missense_variant	Exon 8 of 8	ENST00000345127.9	NP_694571.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRICKLE1	ENST00000345127.9	c.2216C>G	p.Ser739Cys	missense_variant	Exon 8 of 8	1	NM_153026.3	ENSP00000345064.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461878 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 727240

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.030
CADD	Uncertain	23
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.43	T;T;T;T;T;T;T;T;T;T
Eigen	Benign	0.00063
Eigen_PC	Benign	0.062
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.89	.;.;.;.;.;.;.;.;.;D
M_CAP	Benign	0.039	D
MetaRNN	Benign	0.37	T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.087	D
MutationAssessor	Uncertain	2.7	M;M;M;M;M;M;M;M;M;M
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-2.1	N;.;N;.;N;.;.;N;.;N
REVEL	Uncertain	0.42
Sift	Uncertain	0.0010	D;.;D;.;D;.;.;D;.;D
Sift4G	Uncertain	0.0070	D;.;D;.;D;.;.;D;.;D
Polyphen		0.033	B;B;B;B;B;B;B;B;B;B
Vest4		0.38
MutPred		0.38		Loss of disorder (P = 0.0261);Loss of disorder (P = 0.0261);Loss of disorder (P = 0.0261);Loss of disorder (P = 0.0261);Loss of disorder (P = 0.0261);Loss of disorder (P = 0.0261);Loss of disorder (P = 0.0261);Loss of disorder (P = 0.0261);Loss of disorder (P = 0.0261);Loss of disorder (P = 0.0261);
MVP		0.66
MPC		1.0
ClinPred		0.84	D
GERP RS		5.3
Varity_R		0.40
gMVP		0.72

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-42853891;