rs77014998

chr5-37153769-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001384732.1(CPLANE1):c.8344C>A(p.Pro2782Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0105 in 1,612,882 control chromosomes in the GnomAD database, including 115 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0069 (7 hom., cov: 32)
  • Exomes 𝑓: 0.011 (108 hom.)
• Consequence: CPLANE1 NM_001384732.1 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.324

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002856642).
• BP6: Variant 5-37153769-G-T is Benign according to our data. Variant chr5-37153769-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 158055.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-37153769-G-T is described in Lovd as [Benign]. Variant chr5-37153769-G-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0069 (1049/151962) while in subpopulation NFE AF= 0.0111 (752/67960). AF 95% confidence interval is 0.0104. There are 7 homozygotes in gnomad4. There are 500 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CPLANE1	NM_001384732.1	c.8344C>A	p.Pro2782Thr	missense_variant	42/53	ENST00000651892.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CPLANE1	ENST00000651892.2	c.8344C>A	p.Pro2782Thr	missense_variant	42/53		NM_001384732.1	A2

Frequencies

GnomAD3 genomes AF: 0.00691 AC: 1049 AN: 151844 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.00245

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00439

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000835

Gnomad FIN AF: 0.0104

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0111

Gnomad OTH AF: 0.00383

GnomAD3 exomes AF: 0.00662 AC: 1661 AN: 250998 Hom.: 10 AF XY: 0.00663 AC XY: 900 AN XY: 135658

Gnomad AFR exome AF: 0.00197

Gnomad AMR exome AF: 0.00415

Gnomad ASJ exome AF: 0.000794

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000752

Gnomad FIN exome AF: 0.00903

Gnomad NFE exome AF: 0.0107

Gnomad OTH exome AF: 0.00767

GnomAD4 exome AF: 0.0109 AC: 15963 AN: 1460920 Hom.: 108 Cov.: 31 AF XY: 0.0105 AC XY: 7604 AN XY: 726666

Gnomad4 AFR exome AF: 0.00176

Gnomad4 AMR exome AF: 0.00468

Gnomad4 ASJ exome AF: 0.00103

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000951

Gnomad4 FIN exome AF: 0.00826

Gnomad4 NFE exome AF: 0.0132

Gnomad4 OTH exome AF: 0.00774

GnomAD4 genome AF: 0.00690 AC: 1049 AN: 151962 Hom.: 7 Cov.: 32 AF XY: 0.00673 AC XY: 500 AN XY: 74278

Gnomad4 AFR AF: 0.00244

Gnomad4 AMR AF: 0.00439

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00105

Gnomad4 FIN AF: 0.0104

Gnomad4 NFE AF: 0.0111

Gnomad4 OTH AF: 0.00379

Alfa AF: 0.0101 Hom.: 10

Bravo AF: 0.00623

TwinsUK AF: 0.0156 AC: 58

ALSPAC AF: 0.00778 AC: 30

ESP6500AA AF: 0.00454 AC: 20

ESP6500EA AF: 0.0115 AC: 99

ExAC AF: 0.00655 AC: 795

Asia WGS AF: 0.000289 AC: 2 AN: 3478

EpiCase AF: 0.0107

EpiControl AF: 0.0104

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Joubert syndrome 17 Benign:3

Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 09, 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. -
Likely benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 03, 2019	This variant is associated with the following publications: (PMID: 25905921) -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	CPLANE1: BP4, BS1, BS2 -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Apr 04, 2014	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Orofaciodigital syndrome type 6;C3553264:Joubert syndrome 17 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Sep 14, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.76
Cadd	Benign	3.9
Dann	Benign	0.097
DEOGEN2	Benign	0.0031	T;T;T
Eigen	Benign	-0.90
Eigen_PC	Benign	-0.84
FATHMM_MKL	Benign	0.031	N
MetaRNN	Benign	0.0029	T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N;N
PROVEAN	Benign	1.2	N;N;N
REVEL	Benign	0.037
Sift	Benign	1.0	T;T;T
Sift4G	Benign	0.42	T;T;T
Vest4		0.092
MVP		0.22
MPC		0.14
ClinPred		0.00055	T
GERP RS		2.3
Varity_R		0.025
gMVP		0.14

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

LitVar

Other links and lift over

dbSNP: rs77014998; hg19: chr5-37153871; COSMIC: COSV99073217; COSMIC: COSV99073217;