rs191239995

chr5-37226859-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_001384732.1(CPLANE1):c.1736C>T(p.Ala579Val) variant causes a missense change. The variant allele was found at a frequency of 0.000393 in 1,551,136 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A579A) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.00048 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00038 (3 hom.)
• Consequence: CPLANE1 NM_001384732.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 5.39

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010196835).
• BP6: Variant 5-37226859-G-A is Benign according to our data. Variant chr5-37226859-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 261666.We mark this variant Likely_benign, oryginal submissions are: {Benign=4, Uncertain_significance=1}. Variant chr5-37226859-G-A is described in Lovd as [Benign]. Variant chr5-37226859-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00048 (73/152204) while in subpopulation EAS AF= 0.0106 (55/5184). AF 95% confidence interval is 0.00837. There are 1 homozygotes in gnomad4. There are 33 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CPLANE1	NM_001384732.1	c.1736C>T	p.Ala579Val	missense_variant	12/53	ENST00000651892.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CPLANE1	ENST00000651892.2	c.1736C>T	p.Ala579Val	missense_variant	12/53		NM_001384732.1	A2

Frequencies

GnomAD3 genomes AF: 0.000473 AC: 72 AN: 152086 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0104

Gnomad SAS AF: 0.000416

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.000959

GnomAD3 exomes AF: 0.00128 AC: 200 AN: 156256 Hom.: 1 AF XY: 0.00129 AC XY: 107 AN XY: 82644

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000407

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0164

Gnomad SAS exome AF: 0.000441

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000829

Gnomad OTH exome AF: 0.00113

GnomAD4 exome AF: 0.000384 AC: 537 AN: 1398932 Hom.: 3 Cov.: 32 AF XY: 0.000387 AC XY: 267 AN XY: 689914

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000280

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00958

Gnomad4 SAS exome AF: 0.000467

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000899

Gnomad4 OTH exome AF: 0.00102

GnomAD4 genome AF: 0.000480 AC: 73 AN: 152204 Hom.: 1 Cov.: 32 AF XY: 0.000443 AC XY: 33 AN XY: 74414

Gnomad4 AFR AF: 0.000193

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0106

Gnomad4 SAS AF: 0.000416

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.000949

Alfa AF: 0.000146 Hom.: 0

Bravo AF: 0.000725

ExAC AF: 0.000565 AC: 14

Asia WGS AF: 0.00895 AC: 31 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Joubert syndrome 17 Uncertain:1 Benign:1

Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Oct 12, 2017	- -

not specified Benign:2

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

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 23, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 29, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Benign	-0.036	T
BayesDel_noAF	Pathogenic	0.19
Cadd	Pathogenic	26
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.23	T;T
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.93	D
MetaRNN	Benign	0.010	T;T
MetaSVM	Pathogenic	0.93	D
MutationTaster	Benign	0.93	D;D;D
PROVEAN	Uncertain	-2.5	D;D
REVEL	Pathogenic	0.73
Sift	Uncertain	0.010	D;D
Sift4G	Pathogenic	0.0	D;D
Vest4		0.55
MVP		0.66
MPC		0.57
ClinPred		0.053	T
GERP RS		5.1
Varity_R		0.27
gMVP		0.34

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: rs191239995; hg19: chr5-37226961; COSMIC: COSV99949761;