rs565629362

Variant names:

• chr5-37179445-T-C
• rs565629362
• NM_001384732.1:c.5738-2A>G

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_001384732.1(CPLANE1):​c.5738-2A>G variant causes a splice acceptor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000689 in 1,451,648 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: CPLANE1 NM_001384732.1 splice_acceptor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 3.35
• 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 12 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 3.6, offset of -28, new splice context is: cttattttttaaatgatcAGttt. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-37179445-T-C is Pathogenic according to our data. Variant chr5-37179445-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 522892.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CPLANE1	NM_001384732.1	c.5738-2A>G		splice_acceptor_variant, intron_variant	Intron 28 of 52	ENST00000651892.2	NP_001371661.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CPLANE1	ENST00000651892.2	c.5738-2A>G		splice_acceptor_variant, intron_variant	Intron 28 of 52		NM_001384732.1	ENSP00000498265.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.89e-7 AC: 1 AN: 1451648 Hom.: 0 Cov.: 27 AF XY: 0.00 AC XY: 0 AN XY: 722406

African (AFR) AF: 0.00 AC: 0 AN: 33050

American (AMR) AF: 0.00 AC: 0 AN: 43342

Ashkenazi Jewish (ASJ) AF: 0.0000386 AC: 1 AN: 25912

East Asian (EAS) AF: 0.00 AC: 0 AN: 39586

South Asian (SAS) AF: 0.00 AC: 0 AN: 84460

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53348

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5746

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1106182

Other (OTH) AF: 0.00 AC: 0 AN: 60022

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Joubert syndrome Pathogenic:1

Dec 18, 2017

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Benign	-0.10
CADD	Benign	23
DANN	Benign	0.97
Eigen	Pathogenic	0.80
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Uncertain	0.94	D
PhyloP100		3.4
GERP RS		4.8
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.95
SpliceAI score (max)		0.94		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.94		Position offset: -2

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

Other links and lift over

dbSNP: rs565629362; hg19: chr5-37179547;