rs759649053

Positions:

• chr5-37183538-T-C
• chr5-37183538-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP5

The NM_001384732.1(CPLANE1):​c.4643A>G​(p.Asp1548Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CPLANE1 NM_001384732.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 7.10

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-37183538-T-C is Pathogenic according to our data. Variant chr5-37183538-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 427892.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}. Variant chr5-37183538-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CPLANE1	NM_001384732.1	c.4643A>G	p.Asp1548Gly	missense_variant	26/53	ENST00000651892.2	NP_001371661.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CPLANE1	ENST00000651892.2	c.4643A>G	p.Asp1548Gly	missense_variant	26/53		NM_001384732.1	ENSP00000498265	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250836 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135606

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000882

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Joubert syndrome 17 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Institute of Medical Genetics, University of Zurich

May 18, 2017

- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

May 03, 2024

Variant summary: CPLANE1 (alias C5ORF42) c.4643A>G (p.Asp1548Gly) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 250836 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.4643A>G has been reported in the literature in trans with a pathogenic variant in at least 1 individual affected with Joubert Syndrome And Related Disorders (example, Asadollahi_2018, Bonnard_2018). It was also found in the homozygous state in 1 individual undergoing genetic testing for a suspected neurological disorder (Ganapathy_2019) and in as an unspecfied genotype (i.e. zygosity unknown) in 1 individual with Joubert syndrome (Romani_2015). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 29321670, 29605658, 31069529, 25407461). ClinVar contains an entry for this variant (Variation ID: 427892). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.34
BayesDel_addAF	Uncertain	0.087	D
BayesDel_noAF	Benign	-0.11
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.23	T;T;T
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.81	.;T;T
M_CAP	Uncertain	0.15	D
MetaRNN	Uncertain	0.74	D;D;D
MetaSVM	Uncertain	0.13	D
MutationTaster	Benign	1.0	D;D;D
PROVEAN	Uncertain	-3.8	D;D;D
REVEL	Uncertain	0.57
Sift	Uncertain	0.0030	D;D;D
Sift4G	Uncertain	0.0060	D;D;D
Vest4		0.80
MVP		0.69
MPC		0.65
ClinPred		0.99	D
GERP RS		5.4
Varity_R		0.60
gMVP		0.46

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs759649053; hg19: chr5-37183640;