rs149313666

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_ModerateBP6BS1BS2

The NM_001384732.1(CPLANE1):c.5421G>A(p.Lys1807=) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00638 in 1,582,064 control chromosomes in the GnomAD database, including 62 homozygotes. 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 0.0052 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0065 ( 60 hom. )

Consequence

CPLANE1
NM_001384732.1 splice_region, synonymous

Scores

Splicing: ADA: 0.2161

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:10

Conservation

PhyloP100: 2.83

Variant links:

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]

CPLANE1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -11 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.39).

BP6

Variant 5-37182760-C-T is Benign according to our data. Variant chr5-37182760-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 158041.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=5, Likely_benign=3}. Variant chr5-37182760-C-T is described in Lovd as [Benign]. Variant chr5-37182760-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00525 (798/152054) while in subpopulation SAS AF= 0.0129 (62/4806). AF 95% confidence interval is 0.0103. There are 2 homozygotes in gnomad4. There are 405 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CPLANE1	NM_001384732.1 linkuse as main transcript	c.5421G>A	p.Lys1807=	splice_region_variant, synonymous_variant	26/53	ENST00000651892.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CPLANE1	ENST00000651892.2 linkuse as main transcript	c.5421G>A	p.Lys1807=	splice_region_variant, synonymous_variant	26/53		NM_001384732.1	A2

Frequencies

GnomAD3 genomes

AF:

0.00524

AC:

796

AN:

151938

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000774

Gnomad AMI

AF:

0.0340

Gnomad AMR

AF:

0.00360

Gnomad ASJ

AF:

0.0219

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0127

Gnomad FIN

AF:

0.00474

Gnomad MID

AF:

0.0159

Gnomad NFE

AF:

0.00690

Gnomad OTH

AF:

0.00815

GnomAD3 exomes

AF:

0.00697

AC:

1679

AN:

240888

Hom.:

AF XY:

0.00743

AC XY:

968

AN XY:

130242

show subpopulations

Gnomad AFR exome

AF:

0.000440

Gnomad AMR exome

AF:

0.00368

Gnomad ASJ exome

AF:

0.0189

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0133

Gnomad FIN exome

AF:

0.00538

Gnomad NFE exome

AF:

0.00774

Gnomad OTH exome

AF:

0.00528

GnomAD4 exome

AF:

0.00650

AC:

9301

AN:

1430010

Hom.:

Cov.:

AF XY:

0.00677

AC XY:

4827

AN XY:

712692

show subpopulations

Gnomad4 AFR exome

AF:

0.000860

Gnomad4 AMR exome

AF:

0.00377

Gnomad4 ASJ exome

AF:

0.0194

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0139

Gnomad4 FIN exome

AF:

0.00513

Gnomad4 NFE exome

AF:

0.00612

Gnomad4 OTH exome

AF:

0.00719

GnomAD4 genome

AF:

0.00525

AC:

798

AN:

152054

Hom.:

Cov.:

AF XY:

0.00545

AC XY:

405

AN XY:

74338

show subpopulations

Gnomad4 AFR

AF:

0.000771

Gnomad4 AMR

AF:

0.00360

Gnomad4 ASJ

AF:

0.0219

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.0129

Gnomad4 FIN

AF:

0.00474

Gnomad4 NFE

AF:

0.00691

Gnomad4 OTH

AF:

0.00759

Alfa

AF:

0.00731

Hom.:

Bravo

AF:

0.00527

Asia WGS

AF:

0.00635

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:10

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 11, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 22, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not provided

Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jan 31, 2017	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	CPLANE1: BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 22, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Joubert syndrome 17

Uncertain:1Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jun 27, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 10, 2014	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.39

Cadd

Benign

Dann

Benign

0.75

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.22

dbscSNV1_RF

Benign

0.51

SpliceAI score (max)

0.25

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.25

Position offset: 0

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over