chr5-37245583-C-A

Variant names:

• chr5-37245583-C-A
• rs1554117507
• NM_001384732.1:c.233G>T

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PP3 PP5_Moderate

The NM_001384732.1(CPLANE1):​c.233G>T​(p.Gly78Val) variant causes a missense change. The variant allele was found at a frequency of 0.000000734 in 1,362,658 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 (★). Synonymous variant affecting the same amino acid position (i.e. G78G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 7.3e-7 (0 hom.)
• Consequence: CPLANE1 NM_001384732.1 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 5.47
• 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: Uncertain_significance. The variant received 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.797
• PP5: Variant 5-37245583-C-A is Pathogenic according to our data. Variant chr5-37245583-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 537708.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.233G>T	p.Gly78Val	missense_variant	Exon 4 of 53	ENST00000651892.2	NP_001371661.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CPLANE1	ENST00000651892.2	c.233G>T	p.Gly78Val	missense_variant	Exon 4 of 53		NM_001384732.1	ENSP00000498265.2
CPLANE1	ENST00000508244.5	c.233G>T	p.Gly78Val	missense_variant	Exon 3 of 51	5		ENSP00000421690.1
CPLANE1	ENST00000425232.7	n.14G>T		non_coding_transcript_exon_variant	Exon 1 of 30	5		ENSP00000389014.3
CPLANE1	ENST00000675547.1	n.536G>T		non_coding_transcript_exon_variant	Exon 2 of 15

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 7.34e-7 AC: 1 AN: 1362658 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 670230

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 29960

American (AMR) AF: 0.00 AC: 0 AN: 28442

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23952

East Asian (EAS) AF: 0.00 AC: 0 AN: 34862

South Asian (SAS) AF: 0.00 AC: 0 AN: 71188

European-Finnish (FIN) AF: 0.0000206 AC: 1 AN: 48526

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5558

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1063884

Other (OTH) AF: 0.00 AC: 0 AN: 56286

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 30

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Jan 24, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt C5orf42 protein function. This variant has been observed in individual(s) with clinical features of Joubert syndrome (Invitae). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 537708). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with valine at codon 78 of the C5orf42 protein (p.Gly78Val). The glycine residue is weakly conserved and there is a moderate physicochemical difference between glycine and valine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.61
BayesDel_addAF	Uncertain	0.056	T
BayesDel_noAF	Benign	-0.16
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.28	T;T
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.80	.;T
M_CAP	Uncertain	0.19	D
MetaRNN	Pathogenic	0.80	D;D
MetaSVM	Benign	-0.52	T
PhyloP100		5.5
PROVEAN	Pathogenic	-5.6	D;D
REVEL	Uncertain	0.42
Sift	Uncertain	0.0090	D;D
Sift4G	Pathogenic	0.0	D;D
Vest4		0.75
MutPred		0.57		Gain of sheet (P = 0.0266);Gain of sheet (P = 0.0266);
MVP		0.56
MPC		0.64
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.77
gMVP		0.56
Mutation Taster		=142/158	disease causing

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

Other links and lift over

dbSNP: rs1554117507; hg19: chr5-37245685;