rs34737149

chr5-37169119-G-A

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.6905C>T(p.Thr2302Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00169 in 1,614,104 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. T2302T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0018 (7 hom.)
• Consequence: CPLANE1 NM_001384732.1 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.285

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=0.0077658594).
• BP6: Variant 5-37169119-G-A is Benign according to our data. Variant chr5-37169119-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 158050.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-37169119-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00112 (170/152228) while in subpopulation EAS AF= 0.00771 (40/5190). AF 95% confidence interval is 0.00582. There are 0 homozygotes in gnomad4. There are 83 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CPLANE1	NM_001384732.1	c.6905C>T	p.Thr2302Met	missense_variant	34/53	ENST00000651892.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CPLANE1	ENST00000651892.2	c.6905C>T	p.Thr2302Met	missense_variant	34/53		NM_001384732.1	A2

Frequencies

GnomAD3 genomes AF: 0.00112 AC: 170 AN: 152110 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00769

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00160

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00166 AC: 417 AN: 251368 Hom.: 2 AF XY: 0.00169 AC XY: 230 AN XY: 135848

Gnomad AFR exome AF: 0.000431

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00848

Gnomad SAS exome AF: 0.000163

Gnomad FIN exome AF: 0.000185

Gnomad NFE exome AF: 0.00209

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.00175 AC: 2562 AN: 1461876 Hom.: 7 Cov.: 32 AF XY: 0.00174 AC XY: 1264 AN XY: 727240

Gnomad4 AFR exome AF: 0.000329

Gnomad4 AMR exome AF: 0.000157

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00909

Gnomad4 SAS exome AF: 0.000243

Gnomad4 FIN exome AF: 0.000393

Gnomad4 NFE exome AF: 0.00186

Gnomad4 OTH exome AF: 0.00119

GnomAD4 genome AF: 0.00112 AC: 170 AN: 152228 Hom.: 0 Cov.: 32 AF XY: 0.00111 AC XY: 83 AN XY: 74440

Gnomad4 AFR AF: 0.000313

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00771

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.000189

Gnomad4 NFE AF: 0.00160

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00180 Hom.: 2

Bravo AF: 0.00131

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00198 AC: 17

ExAC AF: 0.00188 AC: 228

Asia WGS AF: 0.00318 AC: 11 AN: 3478

EpiCase AF: 0.00131

EpiControl AF: 0.00166

ClinVar

Significance: Benign/Likely 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	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Apr 12, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 22, 2015	- -

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2022	CPLANE1: BP4, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 27, 2021	- -

Joubert syndrome 17 Benign:1

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
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.70
Cadd	Benign	15
Dann	Uncertain	0.99
DEOGEN2	Benign	0.0099	T;T;T
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.45
FATHMM_MKL	Benign	0.67	D
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.0078	T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.99	N;N;N
PROVEAN	Benign	-0.80	N;N;N
REVEL	Benign	0.12
Sift	Uncertain	0.0090	D;D;D
Sift4G	Uncertain	0.051	T;T;D
Vest4		0.073
MVP		0.35
MPC		0.38
ClinPred		0.060	T
GERP RS		0.43
Varity_R		0.025
gMVP		0.14

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs34737149; hg19: chr5-37169221; COSMIC: COSV57056795; COSMIC: COSV57056795;