5-37169067-T-C

Position:

• chr5-37169067-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001384732.1(CPLANE1):​c.6957A>G​(p.Gln2319=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00717 in 1,614,242 control chromosomes in the GnomAD database, including 88 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0066 (12 hom., cov: 32)
  • Exomes 𝑓: 0.0072 (76 hom.)
• Consequence: CPLANE1 NM_001384732.1 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.155

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 5-37169067-T-C is Benign according to our data. Variant chr5-37169067-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 196922.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-37169067-T-C is described in Lovd as [Benign]. Variant chr5-37169067-T-C is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.155 with no splicing effect.
• BA1: GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0589 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CPLANE1	NM_001384732.1	c.6957A>G	p.Gln2319=	synonymous_variant	34/53	ENST00000651892.2	NP_001371661.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CPLANE1	ENST00000651892.2	c.6957A>G	p.Gln2319=	synonymous_variant	34/53		NM_001384732.1	ENSP00000498265	A2

Frequencies

GnomAD3 genomes AF: 0.00662 AC: 1008 AN: 152242 Hom.: 12 Cov.: 32

Gnomad AFR AF: 0.00174

Gnomad AMI AF: 0.0330

Gnomad AMR AF: 0.00693

Gnomad ASJ AF: 0.00835

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00993

Gnomad FIN AF: 0.0146

Gnomad MID AF: 0.0570

Gnomad NFE AF: 0.00758

Gnomad OTH AF: 0.0163

GnomAD3 exomes AF: 0.00750 AC: 1886 AN: 251412 Hom.: 8 AF XY: 0.00803 AC XY: 1091 AN XY: 135884

Gnomad AFR exome AF: 0.00135

Gnomad AMR exome AF: 0.00639

Gnomad ASJ exome AF: 0.0108

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00830

Gnomad FIN exome AF: 0.0150

Gnomad NFE exome AF: 0.00767

Gnomad OTH exome AF: 0.0137

GnomAD4 exome AF: 0.00723 AC: 10565 AN: 1461882 Hom.: 76 Cov.: 32 AF XY: 0.00738 AC XY: 5365 AN XY: 727242

Gnomad4 AFR exome AF: 0.00385

Gnomad4 AMR exome AF: 0.00622

Gnomad4 ASJ exome AF: 0.0102

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00872

Gnomad4 FIN exome AF: 0.0150

Gnomad4 NFE exome AF: 0.00664

Gnomad4 OTH exome AF: 0.00974

GnomAD4 genome AF: 0.00662 AC: 1009 AN: 152360 Hom.: 12 Cov.: 32 AF XY: 0.00711 AC XY: 530 AN XY: 74510

Gnomad4 AFR AF: 0.00175

Gnomad4 AMR AF: 0.00692

Gnomad4 ASJ AF: 0.00835

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00994

Gnomad4 FIN AF: 0.0146

Gnomad4 NFE AF: 0.00759

Gnomad4 OTH AF: 0.0161

Alfa AF: 0.00745 Hom.: 3

Bravo AF: 0.00576

Asia WGS AF: 0.00549 AC: 19 AN: 3478

EpiCase AF: 0.00949

EpiControl AF: 0.00966

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 17, 2014	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 12, 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, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	CPLANE1: BP4, BP7, BS1, BS2 -

Joubert syndrome 17 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -
Likely 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 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
BayesDel_noAF	Benign	-0.75
CADD	Benign	5.3
DANN	Benign	0.35

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs143147192; hg19: chr5-37169169; COSMIC: COSV57071951; COSMIC: COSV57071951;