rs79377186

chr5-37182867-T-C

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.5314A>G(p.Ser1772Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00566 in 1,609,476 control chromosomes in the GnomAD database, including 116 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.016 (49 hom., cov: 32)
  • Exomes 𝑓: 0.0046 (67 hom.)
• Consequence: CPLANE1 NM_001384732.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.518

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=0.0024962723).
• BP6: Variant 5-37182867-T-C is Benign according to our data. Variant chr5-37182867-T-C is described in ClinVar as [Benign]. Clinvar id is 158038.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-37182867-T-C is described in Lovd as [Benign]. Variant chr5-37182867-T-C is described in Lovd as [Likely_pathogenic]. Variant chr5-37182867-T-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0156 (2369/152294) while in subpopulation AFR AF= 0.0468 (1946/41556). AF 95% confidence interval is 0.0451. There are 49 homozygotes in gnomad4. There are 1132 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 49 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CPLANE1	NM_001384732.1	c.5314A>G	p.Ser1772Gly	missense_variant	26/53	ENST00000651892.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CPLANE1	ENST00000651892.2	c.5314A>G	p.Ser1772Gly	missense_variant	26/53		NM_001384732.1	A2

Frequencies

GnomAD3 genomes AF: 0.0155 AC: 2365 AN: 152176 Hom.: 49 Cov.: 32

Gnomad AFR AF: 0.0468

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00714

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0101

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.00331

Gnomad OTH AF: 0.0138

GnomAD3 exomes AF: 0.00697 AC: 1709 AN: 245190 Hom.: 29 AF XY: 0.00676 AC XY: 895 AN XY: 132342

Gnomad AFR exome AF: 0.0486

Gnomad AMR exome AF: 0.00534

Gnomad ASJ exome AF: 0.000516

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00921

Gnomad FIN exome AF: 0.0000932

Gnomad NFE exome AF: 0.00396

Gnomad OTH exome AF: 0.00551

GnomAD4 exome AF: 0.00463 AC: 6742 AN: 1457182 Hom.: 67 Cov.: 32 AF XY: 0.00484 AC XY: 3505 AN XY: 724666

Gnomad4 AFR exome AF: 0.0504

Gnomad4 AMR exome AF: 0.00562

Gnomad4 ASJ exome AF: 0.000425

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0102

Gnomad4 FIN exome AF: 0.000131

Gnomad4 NFE exome AF: 0.00307

Gnomad4 OTH exome AF: 0.00671

GnomAD4 genome AF: 0.0156 AC: 2369 AN: 152294 Hom.: 49 Cov.: 32 AF XY: 0.0152 AC XY: 1132 AN XY: 74462

Gnomad4 AFR AF: 0.0468

Gnomad4 AMR AF: 0.00713

Gnomad4 ASJ AF: 0.000865

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00995

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.00331

Gnomad4 OTH AF: 0.0137

Alfa AF: 0.00620 Hom.: 12

Bravo AF: 0.0177

TwinsUK AF: 0.00351 AC: 13

ALSPAC AF: 0.00182 AC: 7

ESP6500AA AF: 0.0483 AC: 213

ESP6500EA AF: 0.00326 AC: 28

ExAC AF: 0.00789 AC: 958

Asia WGS AF: 0.00346 AC: 12 AN: 3478

EpiCase AF: 0.00371

EpiControl AF: 0.00640

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 23, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Dec 30, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

Joubert syndrome 17 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.63
Cadd	Benign	16
Dann	Uncertain	1.0
DEOGEN2	Benign	0.014	T;T;T
Eigen	Benign	-0.16
Eigen_PC	Benign	-0.23
FATHMM_MKL	Benign	0.61	D
MetaRNN	Benign	0.0025	T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.79	N;N;N
PROVEAN	Benign	-1.8	N;N;N
REVEL	Benign	0.059
Sift	Benign	0.099	T;T;T
Sift4G	Benign	0.20	T;T;T
Vest4		0.16
MVP		0.21
MPC		0.11
ClinPred		0.016	T
GERP RS		3.9
Varity_R		0.12
gMVP		0.15

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: rs79377186; hg19: chr5-37182969;