rs141014620

Variant names:

• chr5-37121709-T-C
• rs141014620
• NM_001384732.1:c.9093A>G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_001384732.1(CPLANE1):​c.9093A>G​(p.Ser3031Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00216 in 1,613,680 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0018 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0022 (8 hom.)
• Consequence: CPLANE1 NM_001384732.1 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 0.213

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 5-37121709-T-C is Benign according to our data. Variant chr5-37121709-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 353417.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Benign=1, Uncertain_significance=1}. Variant chr5-37121709-T-C is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.213 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00182 (277/152368) while in subpopulation NFE AF= 0.00245 (167/68032). AF 95% confidence interval is 0.00215. There are 1 homozygotes in gnomad4. There are 138 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 8 Mitochondrial gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CPLANE1	NM_001384732.1	c.9093A>G	p.Ser3031Ser	synonymous_variant	Exon 49 of 53	ENST00000651892.2	NP_001371661.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CPLANE1	ENST00000651892.2	c.9093A>G	p.Ser3031Ser	synonymous_variant	Exon 49 of 53		NM_001384732.1	ENSP00000498265.2

Frequencies

GnomAD3 genomes AF: 0.00182 AC: 277 AN: 152250 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000458

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00190

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00442

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00245

Gnomad OTH AF: 0.00526

GnomAD3 exomes AF: 0.00169 AC: 424 AN: 251462 Hom.: 2 AF XY: 0.00160 AC XY: 218 AN XY: 135904

Gnomad AFR exome AF: 0.000677

Gnomad AMR exome AF: 0.00162

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000261

Gnomad FIN exome AF: 0.00448

Gnomad NFE exome AF: 0.00209

Gnomad OTH exome AF: 0.00228

GnomAD4 exome AF: 0.00219 AC: 3205 AN: 1461312 Hom.: 8 Cov.: 30 AF XY: 0.00212 AC XY: 1539 AN XY: 727030

Gnomad4 AFR exome AF: 0.000657

Gnomad4 AMR exome AF: 0.00157

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000255

Gnomad4 FIN exome AF: 0.00346

Gnomad4 NFE exome AF: 0.00248

Gnomad4 OTH exome AF: 0.00239

GnomAD4 genome AF: 0.00182 AC: 277 AN: 152368 Hom.: 1 Cov.: 32 AF XY: 0.00185 AC XY: 138 AN XY: 74520

Gnomad4 AFR AF: 0.000457

Gnomad4 AMR AF: 0.00189

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00442

Gnomad4 NFE AF: 0.00245

Gnomad4 OTH AF: 0.00520

Alfa AF: 0.00172 Hom.: 0

Bravo AF: 0.00156

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00294

EpiControl AF: 0.00172

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:3

Jan 28, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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: BP4, BP7 -

Aug 11, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Joubert syndrome 17 Uncertain:1

Jan 12, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	4.0
DANN	Benign	0.68

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: rs141014620; hg19: chr5-37121811; COSMIC: COSV57062162; COSMIC: COSV57062162;