rs10076911

Positions:

• chr5-37173828-A-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001384732.1(CPLANE1):​c.6098T>G​(p.Phe2033Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.116 in 1,613,758 control chromosomes in the GnomAD database, including 12,862 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (2836 hom., cov: 32)
  • Exomes 𝑓: 0.11 (10026 hom.)
• Consequence: CPLANE1 NM_001384732.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.864

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=0.0032223165).
• BP6: Variant 5-37173828-A-C is Benign according to our data. Variant chr5-37173828-A-C is described in ClinVar as [Benign]. Clinvar id is 158048.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-37173828-A-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.306 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CPLANE1	NM_001384732.1	c.6098T>G	p.Phe2033Cys	missense_variant	32/53	ENST00000651892.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CPLANE1	ENST00000651892.2	c.6098T>G	p.Phe2033Cys	missense_variant	32/53		NM_001384732.1	A2

Frequencies

GnomAD3 genomes AF: 0.170 AC: 25915 AN: 152028 Hom.: 2825 Cov.: 32

Gnomad AFR AF: 0.311

Gnomad AMI AF: 0.0351

Gnomad AMR AF: 0.173

Gnomad ASJ AF: 0.149

Gnomad EAS AF: 0.0806

Gnomad SAS AF: 0.108

Gnomad FIN AF: 0.134

Gnomad MID AF: 0.111

Gnomad NFE AF: 0.105

Gnomad OTH AF: 0.172

GnomAD3 exomes AF: 0.134 AC: 33738 AN: 251414 Hom.: 2644 AF XY: 0.127 AC XY: 17286 AN XY: 135880

Gnomad AFR exome AF: 0.311

Gnomad AMR exome AF: 0.188

Gnomad ASJ exome AF: 0.166

Gnomad EAS exome AF: 0.0786

Gnomad SAS exome AF: 0.104

Gnomad FIN exome AF: 0.130

Gnomad NFE exome AF: 0.108

Gnomad OTH exome AF: 0.131

GnomAD4 exome AF: 0.110 AC: 161387 AN: 1461614 Hom.: 10026 Cov.: 31 AF XY: 0.110 AC XY: 79701 AN XY: 727128

Gnomad4 AFR exome AF: 0.314

Gnomad4 AMR exome AF: 0.184

Gnomad4 ASJ exome AF: 0.164

Gnomad4 EAS exome AF: 0.0570

Gnomad4 SAS exome AF: 0.102

Gnomad4 FIN exome AF: 0.129

Gnomad4 NFE exome AF: 0.101

Gnomad4 OTH exome AF: 0.124

GnomAD4 genome AF: 0.171 AC: 25978 AN: 152144 Hom.: 2836 Cov.: 32 AF XY: 0.172 AC XY: 12761 AN XY: 74390

Gnomad4 AFR AF: 0.311

Gnomad4 AMR AF: 0.173

Gnomad4 ASJ AF: 0.149

Gnomad4 EAS AF: 0.0802

Gnomad4 SAS AF: 0.108

Gnomad4 FIN AF: 0.134

Gnomad4 NFE AF: 0.105

Gnomad4 OTH AF: 0.174

Alfa AF: 0.119 Hom.: 3101

Bravo AF: 0.178

TwinsUK AF: 0.0998 AC: 370

ALSPAC AF: 0.0877 AC: 338

ESP6500AA AF: 0.302 AC: 1329

ESP6500EA AF: 0.111 AC: 957

ExAC AF: 0.135 AC: 16398

Asia WGS AF: 0.155 AC: 537 AN: 3478

EpiCase AF: 0.117

EpiControl AF: 0.115

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 14, 2016	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. -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	- -

Joubert syndrome 17 Benign:3

Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.043
BayesDel_addAF	Benign	-0.77	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	6.0
DANN	Benign	0.36
DEOGEN2	Benign	0.0046	T;T;T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.054	N
MetaRNN	Benign	0.0032	T;T;T
MetaSVM	Benign	-0.91	T
MutationTaster	Benign	1.0	P;P;P
PROVEAN	Benign	1.4	N;N;N
REVEL	Benign	0.046
Sift	Benign	0.19	T;T;T
Sift4G	Benign	0.18	T;T;T
Vest4		0.020
MPC		0.17
ClinPred		0.00059	T
GERP RS		3.8
Varity_R		0.056
gMVP		0.21

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: rs10076911; hg19: chr5-37173930; COSMIC: COSV57052574; COSMIC: COSV57052574;