5-37195926-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001384732.1(CPLANE1):c.3743G>A(p.Gly1248Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0363 in 1,612,448 control chromosomes in the GnomAD database, including 1,295 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G1248V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.028 ( 91 hom., cov: 32)

Exomes 𝑓: 0.037 ( 1204 hom. )

Consequence

CPLANE1
NM_001384732.1 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 2.00

Publications

12 publications found

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 Gene-Disease associations (from GenCC):

Joubert syndrome 17
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, ClinGen, G2P, Illumina, Labcorp Genetics (formerly Invitae)
orofaciodigital syndrome type 6
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, G2P
Joubert syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

CPLANE1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0024533272).

BP6

Variant 5-37195926-C-T is Benign according to our data. Variant chr5-37195926-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 158031.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0823 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001384732.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CPLANE1	NM_001384732.1	MANE Select	c.3743G>A	p.Gly1248Asp	missense	Exon 21 of 53	NP_001371661.1
	CPLANE1	NM_023073.4		c.3743G>A	p.Gly1248Asp	missense	Exon 21 of 52	NP_075561.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CPLANE1	ENST00000651892.2	MANE Select	c.3743G>A	p.Gly1248Asp	missense	Exon 21 of 53	ENSP00000498265.2
CPLANE1	ENST00000514429.5	TSL:1	c.887G>A	p.Gly296Asp	missense	Exon 6 of 37	ENSP00000424223.1
CPLANE1	ENST00000509849.5	TSL:1	n.758G>A		non_coding_transcript_exon	Exon 6 of 37	ENSP00000426337.1

Frequencies

GnomAD3 genomes

AF:

0.0282

AC:

4290

AN:

152112

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00765

Gnomad AMI

AF:

0.0307

Gnomad AMR

AF:

0.0311

Gnomad ASJ

AF:

0.0865

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.0394

Gnomad FIN

AF:

0.0232

Gnomad MID

AF:

0.0949

Gnomad NFE

AF:

0.0386

Gnomad OTH

AF:

0.0364

GnomAD2 exomes

AF:

0.0303

AC:

7593

AN:

250198

AF XY:

0.0316

show subpopulations

Gnomad AFR exome

AF:

0.00728

Gnomad AMR exome

AF:

0.0231

Gnomad ASJ exome

AF:

0.0739

Gnomad EAS exome

AF:

0.000109

Gnomad FIN exome

AF:

0.0220

Gnomad NFE exome

AF:

0.0372

Gnomad OTH exome

AF:

0.0408

GnomAD4 exome

AF:

0.0371

AC:

54241

AN:

1460218

Hom.:

1204

Cov.:

AF XY:

0.0371

AC XY:

26922

AN XY:

726416

show subpopulations

African (AFR)

AF:

0.00769

AC:

257

AN:

33424

American (AMR)

AF:

0.0240

AC:

1069

AN:

44494

Ashkenazi Jewish (ASJ)

AF:

0.0746

AC:

1945

AN:

26062

East Asian (EAS)

AF:

0.000152

AC:

AN:

39592

South Asian (SAS)

AF:

0.0329

AC:

2831

AN:

85952

European-Finnish (FIN)

AF:

0.0224

AC:

1195

AN:

53374

Middle Eastern (MID)

AF:

0.0887

AC:

510

AN:

5752

European-Non Finnish (NFE)

AF:

0.0397

AC:

44112

AN:

1111272

Other (OTH)

AF:

0.0384

AC:

2316

AN:

60296

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

2499

4997

7496

9994

12493

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1678

3356

5034

6712

8390

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0282

AC:

4290

AN:

152230

Hom.:

Cov.:

AF XY:

0.0276

AC XY:

2051

AN XY:

74436

show subpopulations

African (AFR)

AF:

0.00763

AC:

317

AN:

41550

American (AMR)

AF:

0.0310

AC:

473

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.0865

AC:

300

AN:

3468

East Asian (EAS)

AF:

0.000386

AC:

AN:

5184

South Asian (SAS)

AF:

0.0394

AC:

190

AN:

4820

European-Finnish (FIN)

AF:

0.0232

AC:

246

AN:

10614

Middle Eastern (MID)

AF:

0.102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0386

AC:

2627

AN:

67998

Other (OTH)

AF:

0.0365

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

213

425

638

850

1063

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

104

156

208

260

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0344

Hom.:

395

Bravo

AF:

0.0272

TwinsUK

AF:

0.0402

AC:

149

ALSPAC

AF:

0.0415

AC:

160

ESP6500AA

AF:

0.00885

AC:

ESP6500EA

AF:

0.0429

AC:

369

ExAC

AF:

0.0302

AC:

3673

Asia WGS

AF:

0.0160

AC:

AN:

3478

EpiCase

AF:

0.0410

EpiControl

AF:

0.0452

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Mar 22, 2016

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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.

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Joubert syndrome 17

Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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.

Sep 21, 2015

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.36

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.021

Eigen

Benign

0.19

Eigen_PC

Benign

0.15

FATHMM_MKL

Benign

0.25

LIST_S2

Benign

0.58

MetaRNN

Benign

0.0025

MetaSVM

Benign

-1.0

PhyloP100

2.0

PROVEAN

Benign

-2.0

REVEL

Benign

0.11

Sift

Benign

0.15

Sift4G

Benign

0.23

Vest4

0.18

MPC

0.33

ClinPred

0.014

GERP RS

5.2

Varity_R

0.10

gMVP

0.13

Mutation Taster

=97/3

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over