12-42459667-C-T

Variant names:

• chr12-42459667-C-T
• rs886049374
• NM_153026.3:c.*142G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_153026.3(PRICKLE1):​c.*142G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000025 in 799,058 control chromosomes in the GnomAD database, with no homozygous occurrence. 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)
  • Exomes 𝑓: 0.0000025 (0 hom.)
• Consequence: PRICKLE1 NM_153026.3 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.469
• Publications: 0 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]

ENSG00000257225 (HGNC:58444):

PPHLN1 (HGNC:19369): (periphilin 1) The protein encoded by this gene is one of the several proteins that become sequentially incorporated into the cornified cell envelope during the terminal differentiation of keratinocyte at the outer layers of epidermis. This protein interacts with periplakin, which is known as a precursor of the cornified cell envelope. The cellular localization pattern and insolubility of this protein suggest that it may play a role in epithelial differentiation and contribute to epidermal integrity and barrier formation. Multiple alternatively spliced transcript variants encoding distinct isoforms have been observed. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).

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.*142G>A		3_prime_UTR	Exon 8 of 8	NP_694571.2	Q96MT3
	PRICKLE1	NM_001144881.2		c.*142G>A		3_prime_UTR	Exon 8 of 8	NP_001138353.1	Q96MT3
	PRICKLE1	NM_001144882.2		c.*142G>A		3_prime_UTR	Exon 8 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.*142G>A		3_prime_UTR	Exon 8 of 8	ENSP00000345064.3	Q96MT3
	ENSG00000257225	ENST00000547824.1	TSL:1	n.302C>T		non_coding_transcript_exon	Exon 1 of 2
	PRICKLE1	ENST00000445766.7	TSL:5	c.*142G>A		3_prime_UTR	Exon 8 of 8	ENSP00000398947.2	Q96MT3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000250 AC: 2 AN: 799058 Hom.: 0 Cov.: 11 AF XY: 0.00000479 AC XY: 2 AN XY: 417656

African (AFR) AF: 0.00 AC: 0 AN: 19724

American (AMR) AF: 0.00 AC: 0 AN: 35726

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18566

East Asian (EAS) AF: 0.00 AC: 0 AN: 36794

South Asian (SAS) AF: 0.00 AC: 0 AN: 62116

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46702

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2704

European-Non Finnish (NFE) AF: 0.00000371 AC: 2 AN: 538624

Other (OTH) AF: 0.00 AC: 0 AN: 38102

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Epilepsy, progressive myoclonic, 1B (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	11
DANN	Benign	0.86
PhyloP100		-0.47

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: rs886049374; hg19: chr12-42853469;