5-37221361-C-T

Variant names:

• chr5-37221361-C-T
• rs863225164
• NM_001384732.1:c.2709G>A

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001384732.1(CPLANE1):​c.2709G>A​(p.Trp903*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000735 in 1,359,976 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.4e-7 (0 hom.)
• Consequence: CPLANE1 NM_001384732.1 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 1.21
• Publications: 0 publications found

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

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-37221361-C-T is Pathogenic according to our data. Variant chr5-37221361-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 217585.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CPLANE1	NM_001384732.1	c.2709G>A	p.Trp903*	stop_gained	Exon 15 of 53	ENST00000651892.2	NP_001371661.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CPLANE1	ENST00000651892.2	c.2709G>A	p.Trp903*	stop_gained	Exon 15 of 53		NM_001384732.1	ENSP00000498265.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.35e-7 AC: 1 AN: 1359976 Hom.: 0 Cov.: 29 AF XY: 0.00000149 AC XY: 1 AN XY: 670206

African (AFR) AF: 0.00 AC: 0 AN: 28900

American (AMR) AF: 0.00 AC: 0 AN: 26800

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23800

East Asian (EAS) AF: 0.00 AC: 0 AN: 33628

South Asian (SAS) AF: 0.00 AC: 0 AN: 71768

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48910

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5524

European-Non Finnish (NFE) AF: 9.40e-7 AC: 1 AN: 1064298

Other (OTH) AF: 0.00 AC: 0 AN: 56348

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Orofaciodigital syndrome type 6;C3553264:Joubert syndrome 17 Pathogenic:1

May 23, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Joubert syndrome 17 Pathogenic:1

Feb 23, 2015

UW Hindbrain Malformation Research Program, University of Washington

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

CPLANE1-related disorder Pathogenic:1

Feb 13, 2023

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The CPLANE1 c.2709G>A variant is predicted to result in premature protein termination (p.Trp903*). This variant was reported along with a second nonsense CPLANE1 variant in an individual with Joubert syndrome (Patient UW195-3 in Table S5, Bachmann-Gagescu et al. 2015. PubMed ID: 26092869). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Nonsense variants in CPLANE1 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	35
DANN	Uncertain	0.99
Eigen	Pathogenic	0.77
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Benign	0.41	N
PhyloP100		1.2
Vest4		0.27
GERP RS		3.8
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs863225164; hg19: chr5-37221463;