rs571875820

chr5-37245480-G-A

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP6

The NM_001384732.1(CPLANE1):c.336C>T(p.Val112=) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000872 in 1,434,258 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 30)
  • Exomes 𝑓: 0.000085 (0 hom.)
• Consequence: CPLANE1 NM_001384732.1 splice_region, synonymous
• Scores: Splicing: ADA: 0.02400
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 1.66

Genes affected

CPLANE1 (HGNC:25801): (ciliogenesis and planar polarity effector complex subunit 1) The protein encoded by this gene has putative coiled-coil domains and may be a transmembrane protein. Defects in this gene are a cause of Joubert syndrome (JBTS). [provided by RefSeq, May 2012]

ACMG classification

Verdict is Likely_benign. Variant got -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.28).
• BP6: Variant 5-37245480-G-A is Benign according to our data. Variant chr5-37245480-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 261669.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}. Variant chr5-37245480-G-A is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CPLANE1	NM_001384732.1	c.336C>T	p.Val112=	splice_region_variant, synonymous_variant	4/53	ENST00000651892.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CPLANE1	ENST00000651892.2	c.336C>T	p.Val112=	splice_region_variant, synonymous_variant	4/53		NM_001384732.1	A2
CPLANE1	ENST00000508244.5	c.336C>T	p.Val112=	splice_region_variant, synonymous_variant	3/51	5		P2
CPLANE1	ENST00000675547.1	n.639C>T		splice_region_variant, non_coding_transcript_exon_variant	2/15
CPLANE1	ENST00000425232.7	c.120C>T	p.Val40=	splice_region_variant, synonymous_variant, NMD_transcript_variant	1/30	5

Frequencies

GnomAD3 genomes AF: 0.000106 AC: 16 AN: 151120 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.000122

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000659

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: 0.000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000396 AC: 4 AN: 101032 Hom.: 0 AF XY: 0.0000368 AC XY: 2 AN XY: 54360

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000174

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000692

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000849 AC: 109 AN: 1283138 Hom.: 0 Cov.: 31 AF XY: 0.0000782 AC XY: 49 AN XY: 626332

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000510

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000314

Gnomad4 SAS exome AF: 0.0000172

Gnomad4 FIN exome AF: 0.0000216

Gnomad4 NFE exome AF: 0.0000980

Gnomad4 OTH exome AF: 0.0000951

GnomAD4 genome AF: 0.000106 AC: 16 AN: 151120 Hom.: 0 Cov.: 30 AF XY: 0.0000678 AC XY: 5 AN XY: 73760

Gnomad4 AFR AF: 0.000122

Gnomad4 AMR AF: 0.0000659

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000216 Hom.: 0

Bravo AF: 0.0000756

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Apr 29, 2022

This sequence change affects codon 112 of the CPLANE1 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the CPLANE1 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs571875820, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with CPLANE1-related conditions. ClinVar contains an entry for this variant (Variation ID: 261669). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.28
Cadd	Benign	13
Dann	Benign	0.83

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.024
dbscSNV1_RF	Benign	0.10
SpliceAI score (max)		0.24		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.24		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs571875820; hg19: chr5-37245582; COSMIC: COSV57075224; COSMIC: COSV57075224;