rs1554117456

Variant names:

• chr5-37245569-C-A
• rs1554117456
• NM_001384732.1:c.247G>T

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001384732.1(CPLANE1):​c.247G>T​(p.Gly83*) variant causes a stop gained change. The variant allele was found at a frequency of 0.000000728 in 1,373,372 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 7.3e-7 (0 hom.)
• Consequence: CPLANE1 NM_001384732.1 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 7.17
• 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, G2P, Labcorp Genetics (formerly Invitae), ClinGen, Illumina
• orofaciodigital syndrome type 6

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

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 18 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 5-37245569-C-A is Pathogenic according to our data. Variant chr5-37245569-C-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 520682.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CPLANE1	NM_001384732.1	MANE Select	c.247G>T	p.Gly83*	stop_gained	Exon 4 of 53	NP_001371661.1	A0A494BZW6
	CPLANE1	NM_023073.4		c.247G>T	p.Gly83*	stop_gained	Exon 4 of 52	NP_075561.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CPLANE1	ENST00000651892.2	MANE Select	c.247G>T	p.Gly83*	stop_gained	Exon 4 of 53	ENSP00000498265.2	A0A494BZW6
	CPLANE1	ENST00000955438.1		c.247G>T	p.Gly83*	stop_gained	Exon 4 of 53	ENSP00000625497.1
	CPLANE1	ENST00000508244.5	TSL:5	c.247G>T	p.Gly83*	stop_gained	Exon 3 of 51	ENSP00000421690.1	Q9H799-1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD2 exomes AF: 0.00000702 AC: 1 AN: 142460 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000101

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 7.28e-7 AC: 1 AN: 1373372 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 676276

African (AFR) AF: 0.00 AC: 0 AN: 30690

American (AMR) AF: 0.00 AC: 0 AN: 31620

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24474

East Asian (EAS) AF: 0.0000286 AC: 1 AN: 34918

South Asian (SAS) AF: 0.00 AC: 0 AN: 73230

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5610

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1067470

Other (OTH) AF: 0.00 AC: 0 AN: 56756

GnomAD4 genome Cov.: 30

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	-	-	Inborn genetic diseases (1)
1	-	-	Joubert syndrome and related disorders (1)
1	-	-	Orofaciodigital syndrome type 6;C3553264:Joubert syndrome 17 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.65
CADD	Pathogenic	36
DANN	Uncertain	0.99
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.99
FATHMM_MKL	Pathogenic	0.99	D
PhyloP100		7.2
Vest4		0.38
GERP RS		5.4
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.26		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.26		Position offset: 29

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

Other links and lift over

dbSNP: rs1554117456; hg19: chr5-37245671;