5-37107584-C-A

Variant names:

• chr5-37107584-C-A
• rs200332492
• NM_001384732.1:c.*18G>T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001384732.1(CPLANE1):​c.*18G>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000494 in 1,593,480 control chromosomes in the GnomAD database, including 5 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 0.00052 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00049 (4 hom.)
• Consequence: CPLANE1 NM_001384732.1 3_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -0.543

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 5-37107584-C-A is Benign according to our data. Variant chr5-37107584-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 261665.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}. Variant chr5-37107584-C-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.000491 (708/1441210) while in subpopulation MID AF= 0.00268 (11/4110). AF 95% confidence interval is 0.0015. There are 4 homozygotes in gnomad4_exome. There are 328 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 4 Mitochondrial gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CPLANE1	NM_001384732.1	c.*18G>T		3_prime_UTR_variant	Exon 53 of 53	ENST00000651892.2	NP_001371661.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CPLANE1	ENST00000651892	c.*18G>T		3_prime_UTR_variant	Exon 53 of 53		NM_001384732.1	ENSP00000498265.2

Frequencies

GnomAD3 genomes AF: 0.000519 AC: 79 AN: 152152 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.0115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000485

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000855 AC: 207 AN: 242208 Hom.: 1 AF XY: 0.000726 AC XY: 95 AN XY: 130820

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000542

Gnomad ASJ exome AF: 0.0137

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000104

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000455

Gnomad OTH exome AF: 0.00120

GnomAD4 exome AF: 0.000491 AC: 708 AN: 1441210 Hom.: 4 Cov.: 32 AF XY: 0.000459 AC XY: 328 AN XY: 714258

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000552

Gnomad4 ASJ exome AF: 0.0124

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000357

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000260

Gnomad4 OTH exome AF: 0.00116

GnomAD4 genome AF: 0.000519 AC: 79 AN: 152270 Hom.: 1 Cov.: 32 AF XY: 0.000457 AC XY: 34 AN XY: 74450

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000261

Gnomad4 ASJ AF: 0.0115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000485

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00218 Hom.: 0

Bravo AF: 0.000597

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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. -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.94
DANN	Benign	0.73

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: rs200332492; hg19: chr5-37107686;