chr5-37164266-T-C

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 10P and 1B. PM2PP5_Very_StrongBP4

The NM_001384732.1(CPLANE1):c.7588+7A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000106 in 1,604,994 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

CPLANE1
NM_001384732.1 splice_region, intron

Scores

Splicing: ADA: 0.0008389

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3U:1

Conservation

PhyloP100: 2.43

Publications

1 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: Likely_pathogenic. The variant received 9 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 5-37164266-T-C is Pathogenic according to our data. Variant chr5-37164266-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 582245.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.47). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CPLANE1	NM_001384732.1 link	c.7588+7A>G		splice_region_variant, intron_variant	Intron 37 of 52	ENST00000651892.2	NP_001371661.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CPLANE1	ENST00000651892.2 link	c.7588+7A>G		splice_region_variant, intron_variant	Intron 37 of 52		NM_001384732.1	ENSP00000498265.2		A0A494BZW6

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152104

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000239

AC:

AN:

251190

AF XY:

0.0000295

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000110

AC:

AN:

1452890

Hom.:

Cov.:

AF XY:

0.0000124

AC XY:

AN XY:

723506

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33286

American (AMR)

AF:

0.000134

AC:

AN:

44658

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26056

East Asian (EAS)

AF:

0.00

AC:

AN:

39620

South Asian (SAS)

AF:

0.00

AC:

AN:

86064

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53408

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5740

European-Non Finnish (NFE)

AF:

0.00000725

AC:

AN:

1103974

Other (OTH)

AF:

0.0000333

AC:

AN:

60084

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.00000657

AC:

AN:

152104

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74296

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41422

American (AMR)

AF:

0.0000655

AC:

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10586

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68026

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000302

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:1Uncertain:1

Mar 30, 2022

GeneDx

Significance:Uncertain significance

Review Status:flagged submission

Collection Method:clinical testing

Identified with a second variant in a patient with Joubert syndrome in the published literature (Enokizono et al., 2017); In-silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 28431631) -

May 14, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change falls in intron 37 of the CPLANE1 gene. It does not directly change the encoded amino acid sequence of the CPLANE1 protein. This variant is present in population databases (rs773662834, gnomAD 0.01%). This variant has been observed in individual(s) with clinical features of Joubert syndrome and related disorders (PMID: 28431631; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 582245). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Joubert syndrome and related disorders

Pathogenic:1

Jul 31, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: CPLANE1 c.7588+7A>G alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Consensus agreement among computation tools predict no significant impact on normal splicing. At least one publication reports experimental evidence that this variant affects mRNA splicing resulting in skipping of exon 37 and truncation of protein leading to potential nonsense-mediated decay (Martnez-Rubio_2023). The variant was absent in 251190 control chromosomes. c.7588+7A>G has been reported in the literature as compound heterozygous genotype in individuals affected with Joubert Syndrome And Related Disorders (Enokizono_2017, Sakamoto_2022, Martnez-Rubio_2023). These data suggesting that the variant is probably associated disease. The following publications have been ascertained in the context of this evaluation (PMID: 28431631, 36305856, 38003592). ClinVar contains an entry for this variant (Variation ID: 582245). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Orofaciodigital syndrome type 6

Pathogenic:1

May 04, 2022

Mendelics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.47

CADD

Benign

(source)

DANN

Benign

0.85

PhyloP100

2.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=28/72

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00084

dbscSNV1_RF

Benign

0.0080

SpliceAI score (max)

0.21

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.21

Position offset: 7

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over