rs149170427

chr5-37198797-G-A

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 12P and 1B. PM2 PM5 PP5_Very_Strong BP4

The NM_001384732.1(CPLANE1):c.3577C>T(p.Arg1193Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000186 in 1,613,954 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1193H) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000017 (0 hom.)
• Consequence: CPLANE1 NM_001384732.1 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 3.20

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]

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr5-37198796-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2150537.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP5: Variant 5-37198797-G-A is Pathogenic according to our data. Variant chr5-37198797-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 265062.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-37198797-G-A is described in Lovd as [Likely_pathogenic]. Variant chr5-37198797-G-A is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.23740909).. Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CPLANE1	NM_001384732.1	c.3577C>T	p.Arg1193Cys	missense_variant	20/53	ENST00000651892.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CPLANE1	ENST00000651892.2	c.3577C>T	p.Arg1193Cys	missense_variant	20/53		NM_001384732.1	A2

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152016 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000770

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000159 AC: 4 AN: 251470 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135916

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000171 AC: 25 AN: 1461820 Hom.: 0 Cov.: 30 AF XY: 0.0000206 AC XY: 15 AN XY: 727208

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000428

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000630

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152134 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 74372

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000772

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000113

ExAC AF: 0.00000824 AC: 1

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Aug 31, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 13, 2016	The R1193C variant in the C5orf42 gene has been reported previously in the presence of another C5orf42 variants in unrelated individuals with clinical diagnoses of OFD IV and Joubert syndrome (Lopez et al., 2014; Ohba et al., 2013). The R1193C variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R1193C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, we interpret R1193C as a likely pathogenic variant. -

Joubert syndrome 17 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Dec 03, 2018

The heterozygous p.Arg1193Cys variant in C5orf42 was identified by our study in the compound heterozygous state, with a pathogenic variant, in one individual with Joubert syndrome. This variant has been identified in 0.005798% (1/17248) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs149170427). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. Computational prediction tools do not provide strong support for or against an impact to the protein. The p.Arg1193Cys variant in C5orf42 has been reported in 6 unrelated Japanese individuals with Joubert syndrome, including 2 individuals with the variant in the homozygous state and 4 individuals with the variant in the compound heterozygous state (PMID: 24091540, 24178751, 27434533, 28431631). The presence of this variant in combination with 4 unique variants (1 reported by our study, 1 reported pathogenic in ClinVar, 2 reported in the literature) and in an individual with Joubert syndrome increases the likelihood that the p.Arg1193Cys variant is pathogenic. In summary, although additional studies are required to fully establish its clinical significance, the p.Arg1193Cys variant is likely pathogenic. ACMG/AMP Criteria applied: PM2, PM3_Strong (Richards 2015). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Benign	-0.015	T
BayesDel_noAF	Benign	-0.090
Cadd	Pathogenic	28
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.28	T;T;T
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.91	D
M_CAP	Uncertain	0.27	D
MetaRNN	Benign	0.24	T;T;T
MetaSVM	Benign	-0.89	T
MutationTaster	Benign	1.0	D;D;D
PROVEAN	Uncertain	-4.4	D;D;D
REVEL	Uncertain	0.31
Sift	Uncertain	0.0020	D;D;D
Sift4G	Pathogenic	0.0010	D;D;D
Vest4		0.88
MVP		0.48
MPC		0.67
ClinPred		0.99	D
GERP RS		3.3
Varity_R		0.38
gMVP		0.57

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs149170427; hg19: chr5-37198899; COSMIC: COSV105857411;