rs76245173

chr5-37180915-T-Cchr5-37180915-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001384732.1(CPLANE1):c.5512A>G(p.Thr1838Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00596 in 1,613,928 control chromosomes in the GnomAD database, including 133 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.017 (57 hom., cov: 32)
  • Exomes 𝑓: 0.0048 (76 hom.)
• Consequence: CPLANE1 NM_001384732.1 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -1.24

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=0.0025082827).
• BP6: Variant 5-37180915-T-C is Benign according to our data. Variant chr5-37180915-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 158042.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-37180915-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0506 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CPLANE1	NM_001384732.1	c.5512A>G	p.Thr1838Ala	missense_variant	27/53	ENST00000651892.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CPLANE1	ENST00000651892.2	c.5512A>G	p.Thr1838Ala	missense_variant	27/53		NM_001384732.1	A2

Frequencies

GnomAD3 genomes AF: 0.0172 AC: 2615 AN: 152126 Hom.: 57 Cov.: 32

Gnomad AFR AF: 0.0525

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00826

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00954

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.00331

Gnomad OTH AF: 0.0162

GnomAD3 exomes AF: 0.00730 AC: 1836 AN: 251404 Hom.: 33 AF XY: 0.00699 AC XY: 950 AN XY: 135884

Gnomad AFR exome AF: 0.0547

Gnomad AMR exome AF: 0.00529

Gnomad ASJ exome AF: 0.000496

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00895

Gnomad FIN exome AF: 0.0000925

Gnomad NFE exome AF: 0.00395

Gnomad OTH exome AF: 0.00554

GnomAD4 exome AF: 0.00479 AC: 6998 AN: 1461684 Hom.: 76 Cov.: 30 AF XY: 0.00498 AC XY: 3620 AN XY: 727152

Gnomad4 AFR exome AF: 0.0563

Gnomad4 AMR exome AF: 0.00570

Gnomad4 ASJ exome AF: 0.000421

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0102

Gnomad4 FIN exome AF: 0.000131

Gnomad4 NFE exome AF: 0.00306

Gnomad4 OTH exome AF: 0.00719

GnomAD4 genome AF: 0.0172 AC: 2619 AN: 152244 Hom.: 57 Cov.: 32 AF XY: 0.0169 AC XY: 1256 AN XY: 74440

Gnomad4 AFR AF: 0.0524

Gnomad4 AMR AF: 0.00825

Gnomad4 ASJ AF: 0.000864

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00934

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.00331

Gnomad4 OTH AF: 0.0161

Alfa AF: 0.00511 Hom.: 7

Bravo AF: 0.0199

TwinsUK AF: 0.00351 AC: 13

ALSPAC AF: 0.00182 AC: 7

ESP6500AA AF: 0.0561 AC: 247

ESP6500EA AF: 0.00326 AC: 28

ExAC AF: 0.00847 AC: 1029

Asia WGS AF: 0.00346 AC: 12 AN: 3478

EpiCase AF: 0.00371

EpiControl AF: 0.00640

ClinVar

Significance: Benign/Likely 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	PreventionGenetics, part of Exact Sciences	-	- -
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. -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	- -

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

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Sep 15, 2021

- -

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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.76	T
BayesDel_noAF	Benign	-0.82
Cadd	Benign	0.010
Dann	Benign	0.12
DEOGEN2	Benign	0.011	T;T;T
Eigen	Benign	-2.3
Eigen_PC	Benign	-2.4
FATHMM_MKL	Benign	0.0072	N
MetaRNN	Benign	0.0025	T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N;N
PROVEAN	Benign	-0.95	N;N;N
REVEL	Benign	0.048
Sift	Benign	1.0	T;T;T
Sift4G	Benign	0.96	T;T;T
Vest4		0.092
MVP		0.014
MPC		0.12
ClinPred		0.0034	T
GERP RS		-12
Varity_R		0.032
gMVP		0.34

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs76245173; hg19: chr5-37181017;