chr5-37183290-A-AT

Variant names:

• chr5-37183290-A-AT
• rs1554083251
• NM_001384732.1:c.4890dupA

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_001384732.1(CPLANE1):​c.4890dupA​(p.Ser1631IlefsTer6) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,248 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. K1630K) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CPLANE1 NM_001384732.1 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: -0.0550
• Publications: 0 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: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-37183290-A-AT is Pathogenic according to our data. Variant chr5-37183290-A-AT is described in CliVar as Pathogenic. Clinvar id is 473148.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-37183290-A-AT is described in CliVar as Pathogenic. Clinvar id is 473148.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-37183290-A-AT is described in CliVar as Pathogenic. Clinvar id is 473148.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-37183290-A-AT is described in CliVar as Pathogenic. Clinvar id is 473148.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-37183290-A-AT is described in CliVar as Pathogenic. Clinvar id is 473148.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-37183290-A-AT is described in CliVar as Pathogenic. Clinvar id is 473148.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-37183290-A-AT is described in CliVar as Pathogenic. Clinvar id is 473148.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CPLANE1	NM_001384732.1	c.4890dupA	p.Ser1631IlefsTer6	frameshift_variant	Exon 26 of 53	ENST00000651892.2	NP_001371661.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CPLANE1	ENST00000651892.2	c.4890dupA	p.Ser1631IlefsTer6	frameshift_variant	Exon 26 of 53		NM_001384732.1	ENSP00000498265.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461248 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726916

African (AFR) AF: 0.00 AC: 0 AN: 33452

American (AMR) AF: 0.00 AC: 0 AN: 44662

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39640

South Asian (SAS) AF: 0.00 AC: 0 AN: 86138

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53248

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111856

Other (OTH) AF: 0.00 AC: 0 AN: 60368

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

May 03, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change inserts 1 nucleotide in exon 26 of the C5orf42 mRNA (c.4890dupA), causing a frameshift at codon 1631. This creates a premature translational stop signal (p.Ser1631Ilefs*6) and is expected to result in an absent or disrupted protein product. While this particular variant has not been reported in the literature, loss-of-function variants in C5orf42 are known to be pathogenic (PMID: 22425360). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.055
Mutation Taster		=1/199	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1554083251; hg19: chr5-37183392;