5-37125240-T-G

Variant names:

• chr5-37125240-T-G
• rs199810663
• NM_001384732.1:c.8958+4A>C

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 1P and 9B. PP3 BP6 BS1 BS2

The NM_001384732.1(CPLANE1):​c.8958+4A>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00311 in 1,610,100 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0023 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0032 (10 hom.)
• Consequence: CPLANE1 NM_001384732.1 splice_region, intron
• Scores: Splicing: ADA: 0.9927
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:6
• Conservation: PhyloP100: 1.63
• Publications: 1 publications found

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]

CPLANE1 Gene-Disease associations (from GenCC):

• Joubert syndrome 17

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, ClinGen, G2P, Illumina, Labcorp Genetics (formerly Invitae)
• orofaciodigital syndrome type 6

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, G2P
• Joubert syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• BP6: Variant 5-37125240-T-G is Benign according to our data. Variant chr5-37125240-T-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 197551.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00234 (357/152350) while in subpopulation AMR AF = 0.00314 (48/15296). AF 95% confidence interval is 0.00276. There are 2 homozygotes in GnomAd4. There are 168 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001384732.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CPLANE1	NM_001384732.1	MANE Select	c.8958+4A>C		splice_region intron	N/A	NP_001371661.1
	CPLANE1	NM_023073.4		c.8796+4A>C		splice_region intron	N/A	NP_075561.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CPLANE1	ENST00000651892.2	MANE Select	c.8958+4A>C		splice_region intron	N/A	ENSP00000498265.2
	CPLANE1	ENST00000514429.5	TSL:1	c.5994+4A>C		splice_region intron	N/A	ENSP00000424223.1
	CPLANE1	ENST00000509849.5	TSL:1	n.*300+4A>C		splice_region intron	N/A	ENSP00000426337.1

Frequencies

GnomAD3 genomes AF: 0.00235 AC: 358 AN: 152232 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000603

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00314

Gnomad ASJ AF: 0.0170

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00312

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00260 AC: 645 AN: 248302 AF XY: 0.00257

Gnomad AFR exome AF: 0.000371

Gnomad AMR exome AF: 0.00174

Gnomad ASJ exome AF: 0.0146

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000278

Gnomad NFE exome AF: 0.00311

Gnomad OTH exome AF: 0.00397

GnomAD4 exome AF: 0.00319 AC: 4656 AN: 1457750 Hom.: 10 Cov.: 31 AF XY: 0.00315 AC XY: 2287 AN XY: 725030

African (AFR) AF: 0.000422 AC: 14 AN: 33184

American (AMR) AF: 0.00169 AC: 74 AN: 43672

Ashkenazi Jewish (ASJ) AF: 0.0150 AC: 390 AN: 26046

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39574

South Asian (SAS) AF: 0.00124 AC: 106 AN: 85418

European-Finnish (FIN) AF: 0.000244 AC: 13 AN: 53344

Middle Eastern (MID) AF: 0.00574 AC: 33 AN: 5754

European-Non Finnish (NFE) AF: 0.00337 AC: 3744 AN: 1110510

Other (OTH) AF: 0.00466 AC: 281 AN: 60248

GnomAD4 genome AF: 0.00234 AC: 357 AN: 152350 Hom.: 2 Cov.: 32 AF XY: 0.00225 AC XY: 168 AN XY: 74504

African (AFR) AF: 0.000601 AC: 25 AN: 41582

American (AMR) AF: 0.00314 AC: 48 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0170 AC: 59 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4824

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10628

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00310 AC: 211 AN: 68040

Other (OTH) AF: 0.00284 AC: 6 AN: 2114

Alfa AF: 0.00335 Hom.: 1

Bravo AF: 0.00239

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00458

EpiControl AF: 0.00463

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:3

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 13, 2015

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Sep 15, 2016

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Dec 21, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CPLANE1: PP3, BS2

not specified Uncertain:1 Benign:1

Nov 06, 2015

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

May 31, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: CPLANE1 c.8796+4A>C alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Three predict the variant weakens the canonical 5' donor site. One predict the variant no significant impact on splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0025 in 279710 control chromosomes, predominantly at a frequency of 0.0031 within the Non-Finnish European subpopulation in the gnomAD database, including 1 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 2-fold of the estimated maximal expected allele frequency for a pathogenic variant in CPLANE1 causing Joubert Syndrome And Related Disorders phenotype (0.0015). To our knowledge, no occurrence of c.8796+4A>C in individuals affected with Joubert Syndrome And Related Disorders and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 197551). Based on the evidence outlined above, the variant was classified as benign.

Joubert syndrome 17 Uncertain:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

CPLANE1-related disorder Benign:1

Jun 24, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

Intellectual disability Benign:1

Apr 17, 2019

Cambridge Genomics Laboratory, East Genomic Laboratory Hub, NHS Genomic Medicine Service

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.28
CADD	Benign	22
DANN	Benign	0.93
PhyloP100		1.6
Mutation Taster		=80/20	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Pathogenic	0.74
SpliceAI score (max)		0.89		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.89		Position offset: -16

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs199810663; hg19: chr5-37125342;