5-37182852-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001384732.1(CPLANE1):c.5329G>A(p.Val1777Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00133 in 1,613,058 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0052 (4 hom., cov: 32)
  • Exomes 𝑓: 0.00093 (8 hom.)
• Consequence: CPLANE1 NM_001384732.1 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 2.77

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007766694).
• BP6: Variant 5-37182852-C-T is Benign according to our data. Variant chr5-37182852-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 261673.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-37182852-C-T is described in Lovd as [Benign]. Variant chr5-37182852-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00518 (789/152246) while in subpopulation AFR AF= 0.0154 (638/41560). AF 95% confidence interval is 0.0144. There are 4 homozygotes in gnomad4. There are 394 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CPLANE1	NM_001384732.1	c.5329G>A	p.Val1777Ile	missense_variant	26/53	ENST00000651892.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CPLANE1	ENST00000651892.2	c.5329G>A	p.Val1777Ile	missense_variant	26/53		NM_001384732.1	A2

Frequencies

GnomAD3 genomes AF: 0.00519 AC: 789 AN: 152128 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.0154

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00511

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000823

Gnomad OTH AF: 0.00670

GnomAD3 exomes AF: 0.00184 AC: 459 AN: 249704 Hom.: 1 AF XY: 0.00147 AC XY: 198 AN XY: 134924

Gnomad AFR exome AF: 0.0155

Gnomad AMR exome AF: 0.00275

Gnomad ASJ exome AF: 0.000100

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000199

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000795

Gnomad OTH exome AF: 0.00262

GnomAD4 exome AF: 0.000933 AC: 1363 AN: 1460812 Hom.: 8 Cov.: 32 AF XY: 0.000859 AC XY: 624 AN XY: 726670

Gnomad4 AFR exome AF: 0.0142

Gnomad4 AMR exome AF: 0.00288

Gnomad4 ASJ exome AF: 0.0000767

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000151

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000506

Gnomad4 OTH exome AF: 0.00215

GnomAD4 genome AF: 0.00518 AC: 789 AN: 152246 Hom.: 4 Cov.: 32 AF XY: 0.00529 AC XY: 394 AN XY: 74440

Gnomad4 AFR AF: 0.0154

Gnomad4 AMR AF: 0.00510

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000809

Gnomad4 OTH AF: 0.00663

Alfa AF: 0.00114 Hom.: 4

Bravo AF: 0.00588

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0145 AC: 64

ESP6500EA AF: 0.00105 AC: 9

ExAC AF: 0.00194 AC: 236

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000981

EpiControl AF: 0.000830

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 06, 2019	- -

Joubert syndrome 17 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.57
Cadd	Benign	22
Dann	Uncertain	1.0
DEOGEN2	Benign	0.031	T;T;T
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Pathogenic	0.98	D
MetaRNN	Benign	0.0078	T;T;T
MetaSVM	Benign	-0.99	T
MutationTaster	Benign	0.94	D;D;D
PROVEAN	Benign	-0.54	N;N;N
REVEL	Benign	0.096
Sift	Uncertain	0.012	D;D;D
Sift4G	Uncertain	0.045	D;D;D
Vest4		0.29
MVP		0.51
MPC		0.30
ClinPred		0.021	T
GERP RS		5.1
Varity_R		0.12
gMVP		0.20

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: rs142777778; hg19: chr5-37182954;