rs756856188

Variant names:

• chr5-37244521-C-T
• rs756856188
• NM_001384732.1:c.424G>A

Your query was ambiguous. Multiple possible variants found:

• chr5-37244521-C-T
• chr5-37244521-C-G

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PP5_Very_Strong

The NM_001384732.1(CPLANE1):​c.424G>A​(p.Glu142Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000258 in 1,551,530 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.00013 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00027 (1 hom.)
• Consequence: CPLANE1 NM_001384732.1 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9 U:2
• Conservation: PhyloP100: 6.93
• Publications: 2 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: Likely_pathogenic. The variant received 8 ACMG points.

• PP5: Variant 5-37244521-C-T is Pathogenic according to our data. Variant chr5-37244521-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 217592.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.424G>A	p.Glu142Lys	missense	Exon 5 of 53	NP_001371661.1	A0A494BZW6
	CPLANE1	NM_023073.4		c.424G>A	p.Glu142Lys	missense	Exon 5 of 52	NP_075561.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CPLANE1	ENST00000651892.2	MANE Select	c.424G>A	p.Glu142Lys	missense	Exon 5 of 53	ENSP00000498265.2	A0A494BZW6
	CPLANE1	ENST00000955438.1		c.424G>A	p.Glu142Lys	missense	Exon 5 of 53	ENSP00000625497.1
	CPLANE1	ENST00000508244.5	TSL:5	c.424G>A	p.Glu142Lys	missense	Exon 4 of 51	ENSP00000421690.1	Q9H799-1

Frequencies

GnomAD3 genomes AF: 0.000132 AC: 20 AN: 151956 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000725

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000121 AC: 19 AN: 157586 AF XY: 0.0000960

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000294

Gnomad OTH exome AF: 0.000225

GnomAD4 exome AF: 0.000272 AC: 380 AN: 1399574 Hom.: 1 Cov.: 31 AF XY: 0.000252 AC XY: 174 AN XY: 690282

African (AFR) AF: 0.00 AC: 0 AN: 31598

American (AMR) AF: 0.00 AC: 0 AN: 35704

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25180

East Asian (EAS) AF: 0.00 AC: 0 AN: 35720

South Asian (SAS) AF: 0.00 AC: 0 AN: 79234

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49384

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5700

European-Non Finnish (NFE) AF: 0.000333 AC: 359 AN: 1078978

Other (OTH) AF: 0.000362 AC: 21 AN: 58076

GnomAD4 genome AF: 0.000132 AC: 20 AN: 151956 Hom.: 0 Cov.: 31 AF XY: 0.000135 AC XY: 10 AN XY: 74192

African (AFR) AF: 0.0000725 AC: 3 AN: 41364

American (AMR) AF: 0.00 AC: 0 AN: 15234

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4796

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10576

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000250 AC: 17 AN: 68010

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.000345 Hom.: 0

Bravo AF: 0.000159

ExAC AF: 0.0000805 AC: 2

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	Joubert syndrome 17 (3)
3	-	-	not provided (3)
1	-	-	CPLANE1-related disorder (1)
1	-	-	Joubert syndrome and related disorders (1)
-	1	-	Nephronophthisis (1)
-	1	-	not specified (1)
1	-	-	Orofaciodigital syndrome type 6;C3553264:Joubert syndrome 17 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.57
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Uncertain	-0.080
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.17	T
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.86	D
M_CAP	Uncertain	0.085	D
MetaRNN	Uncertain	0.61	D
MetaSVM	Benign	-0.41	T
PhyloP100		6.9
PROVEAN	Uncertain	-2.7	D
REVEL	Uncertain	0.31
Sift	Uncertain	0.0040	D
Sift4G	Pathogenic	0.0	D
Vest4		0.92
MVP		0.67
MPC		0.61
ClinPred		0.34	T
GERP RS		5.7
Varity_R		0.53
gMVP		0.55
Mutation Taster		=180/120	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: rs756856188; hg19: chr5-37244623; COSMIC: COSV57059238; COSMIC: COSV57059238;