rs1554117507

Variant names:

• chr5-37245583-C-A
• rs1554117507
• NM_001384732.1:c.233G>T

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PP3 PP5_Moderate

The NM_001384732.1(CPLANE1):​c.233G>T​(p.Gly78Val) variant causes a missense change. The variant allele was found at a frequency of 0.000000734 in 1,362,658 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 Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. G78G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 7.3e-7 (0 hom.)
• Consequence: CPLANE1 NM_001384732.1 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 5.47
• 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: Uncertain_significance. The variant received 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.797
• PP5: Variant 5-37245583-C-A is Pathogenic according to our data. Variant chr5-37245583-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 537708.Status of the report is criteria_provided_single_submitter, 1 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CPLANE1	NM_001384732.1	MANE Select	c.233G>T	p.Gly78Val	missense	Exon 4 of 53	NP_001371661.1
	CPLANE1	NM_023073.4		c.233G>T	p.Gly78Val	missense	Exon 4 of 52	NP_075561.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CPLANE1	ENST00000651892.2	MANE Select	c.233G>T	p.Gly78Val	missense	Exon 4 of 53	ENSP00000498265.2
	CPLANE1	ENST00000955438.1		c.233G>T	p.Gly78Val	missense	Exon 4 of 53	ENSP00000625497.1
	CPLANE1	ENST00000508244.5	TSL:5	c.233G>T	p.Gly78Val	missense	Exon 3 of 51	ENSP00000421690.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 7.34e-7 AC: 1 AN: 1362658 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 670230

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 29960

American (AMR) AF: 0.00 AC: 0 AN: 28442

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23952

East Asian (EAS) AF: 0.00 AC: 0 AN: 34862

South Asian (SAS) AF: 0.00 AC: 0 AN: 71188

European-Finnish (FIN) AF: 0.0000206 AC: 1 AN: 48526

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5558

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1063884

Other (OTH) AF: 0.00 AC: 0 AN: 56286

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 30

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.61
BayesDel_addAF	Uncertain	0.056	T
BayesDel_noAF	Benign	-0.16
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.28	T
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.80	T
M_CAP	Uncertain	0.19	D
MetaRNN	Pathogenic	0.80	D
MetaSVM	Benign	-0.52	T
PhyloP100		5.5
PROVEAN	Pathogenic	-5.6	D
REVEL	Uncertain	0.42
Sift	Uncertain	0.0090	D
Sift4G	Pathogenic	0.0	D
Vest4		0.75
MutPred		0.57		Gain of sheet (P = 0.0266)
MVP		0.56
MPC		0.64
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.77
gMVP		0.56
Mutation Taster		=142/158	disease causing

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: rs1554117507; hg19: chr5-37245685;