rs16903518

Positions:

• chr5-37158261-G-A

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.7775C>T​(p.Pro2592Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00394 in 1,613,798 control chromosomes in the GnomAD database, including 236 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P2592A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.021 (127 hom., cov: 32)
  • Exomes 𝑓: 0.0021 (109 hom.)
• Consequence: CPLANE1 NM_001384732.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.96

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=0.0019657612).
• BP6: Variant 5-37158261-G-A is Benign according to our data. Variant chr5-37158261-G-A is described in ClinVar as [Benign]. Clinvar id is 158052.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-37158261-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0727 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CPLANE1	NM_001384732.1	c.7775C>T	p.Pro2592Leu	missense_variant	39/53	ENST00000651892.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CPLANE1	ENST00000651892.2	c.7775C>T	p.Pro2592Leu	missense_variant	39/53		NM_001384732.1	A2

Frequencies

GnomAD3 genomes AF: 0.0211 AC: 3203 AN: 152034 Hom.: 120 Cov.: 32

Gnomad AFR AF: 0.0743

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00577

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.0129

GnomAD3 exomes AF: 0.00548 AC: 1378 AN: 251400 Hom.: 49 AF XY: 0.00393 AC XY: 534 AN XY: 135886

Gnomad AFR exome AF: 0.0764

Gnomad AMR exome AF: 0.00306

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000106

Gnomad OTH exome AF: 0.00212

GnomAD4 exome AF: 0.00214 AC: 3126 AN: 1461646 Hom.: 109 Cov.: 31 AF XY: 0.00188 AC XY: 1367 AN XY: 727124

Gnomad4 AFR exome AF: 0.0771

Gnomad4 AMR exome AF: 0.00347

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000278

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000342

Gnomad4 OTH exome AF: 0.00508

GnomAD4 genome AF: 0.0213 AC: 3236 AN: 152152 Hom.: 127 Cov.: 32 AF XY: 0.0205 AC XY: 1524 AN XY: 74380

Gnomad4 AFR AF: 0.0749

Gnomad4 AMR AF: 0.00576

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000176

Gnomad4 OTH AF: 0.0128

Alfa AF: 0.00386 Hom.: 32

Bravo AF: 0.0238

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0772 AC: 340

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00689 AC: 837

Asia WGS AF: 0.00809 AC: 28 AN: 3476

EpiCase AF: 0.000164

EpiControl AF: 0.000178

ClinVar

Significance: Benign

Submissions summary: Benign:5

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	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 03, 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. -

Joubert syndrome 17 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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 30, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	15
DANN	Benign	0.97
DEOGEN2	Benign	0.14	T;T;T
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.60
FATHMM_MKL	Benign	0.37	N
MetaRNN	Benign	0.0020	T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N;N
PROVEAN	Uncertain	-4.0	D;D;D
REVEL	Benign	0.053
Sift	Benign	0.048	D;D;D
Sift4G	Uncertain	0.0040	D;D;D
Vest4		0.089
MVP		0.39
MPC		0.13
ClinPred		0.010	T
GERP RS		3.0
Varity_R		0.068
gMVP		0.20

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs16903518; hg19: chr5-37158363;