rs554483416

chr5-37213624-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PM1 PM2 BP4_Strong

The NM_001384732.1(CPLANE1):c.2855A>G(p.Asn952Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000114 in 1,548,412 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 Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00053 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000069 (0 hom.)
• Consequence: CPLANE1 NM_001384732.1 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 7.11

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 0 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_001384732.1
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.039601386).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CPLANE1	NM_001384732.1	c.2855A>G	p.Asn952Ser	missense_variant	16/53	ENST00000651892.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CPLANE1	ENST00000651892.2	c.2855A>G	p.Asn952Ser	missense_variant	16/53		NM_001384732.1	A2

Frequencies

GnomAD3 genomes AF: 0.000539 AC: 82 AN: 152108 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00179

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000944

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.000958

GnomAD3 exomes AF: 0.000115 AC: 18 AN: 155860 Hom.: 0 AF XY: 0.0000848 AC XY: 7 AN XY: 82534

Gnomad AFR exome AF: 0.00126

Gnomad AMR exome AF: 0.0000825

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000442

Gnomad FIN exome AF: 0.000119

Gnomad NFE exome AF: 0.0000495

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000688 AC: 96 AN: 1396186 Hom.: 0 Cov.: 30 AF XY: 0.0000770 AC XY: 53 AN XY: 688568

Gnomad4 AFR exome AF: 0.00155

Gnomad4 AMR exome AF: 0.0000563

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000254

Gnomad4 FIN exome AF: 0.0000813

Gnomad4 NFE exome AF: 0.0000297

Gnomad4 OTH exome AF: 0.000121

GnomAD4 genome AF: 0.000532 AC: 81 AN: 152226 Hom.: 0 Cov.: 32 AF XY: 0.000551 AC XY: 41 AN XY: 74428

Gnomad4 AFR AF: 0.00176

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000944

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.000948

Alfa AF: 0.000210 Hom.: 0

Bravo AF: 0.000669

ExAC AF: 0.000238 AC: 6

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 02, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Oct 04, 2022	This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 952 of the CPLANE1 protein (p.Asn952Ser). This variant is present in population databases (rs554483416, gnomAD 0.1%). This variant has not been reported in the literature in individuals affected with CPLANE1-related conditions. ClinVar contains an entry for this variant (Variation ID: 569892). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on CPLANE1 protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 10, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.39
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Benign	0.29	T;T
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Benign	0.046	D
MetaRNN	Benign	0.040	T;T
MetaSVM	Benign	-0.65	T
MutationTaster	Benign	0.93	D;D;D
PROVEAN	Uncertain	-3.4	D;D
REVEL	Benign	0.27
Sift	Uncertain	0.010	D;D
Sift4G	Pathogenic	0.0	D;D
Vest4		0.50
MVP		0.68
MPC		0.50
ClinPred		0.13	T
GERP RS		5.4
Varity_R		0.32
gMVP		0.13

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

Publications

LitVar

Other links and lift over

dbSNP: rs554483416; hg19: chr5-37213726;