chr5-37221459-G-A

Variant names:

• chr5-37221459-G-A
• rs760906097
• NM_001384732.1:c.2611C>T

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM1 PM2 PM5 PP5_Very_Strong

The NM_001384732.1(CPLANE1):​c.2611C>T​(p.Arg871Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000244 in 1,353,702 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R871H) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000024 (0 hom.)
• Consequence: CPLANE1 NM_001384732.1 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3 U:1 O:1
• Conservation: PhyloP100: 5.13
• 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 14 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_001384732.1
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr5-37221458-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 2418530.
• PP5: Variant 5-37221459-G-A is Pathogenic according to our data. Variant chr5-37221459-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 217589.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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CPLANE1	NM_001384732.1	MANE Select	c.2611C>T	p.Arg871Cys	missense	Exon 15 of 53	NP_001371661.1
	CPLANE1	NM_023073.4		c.2611C>T	p.Arg871Cys	missense	Exon 15 of 52	NP_075561.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CPLANE1	ENST00000651892.2	MANE Select	c.2611C>T	p.Arg871Cys	missense	Exon 15 of 53	ENSP00000498265.2
	CPLANE1	ENST00000508244.5	TSL:5	c.2611C>T	p.Arg871Cys	missense	Exon 14 of 51	ENSP00000421690.1
	CPLANE1	ENST00000425232.7	TSL:5	n.*1940C>T		non_coding_transcript_exon	Exon 12 of 30	ENSP00000389014.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000355 AC: 4 AN: 112684 AF XY: 0.0000499

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000160

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000420

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000244 AC: 33 AN: 1353702 Hom.: 0 Cov.: 29 AF XY: 0.0000285 AC XY: 19 AN XY: 667014

African (AFR) AF: 0.00 AC: 0 AN: 28462

American (AMR) AF: 0.00 AC: 0 AN: 23612

Ashkenazi Jewish (ASJ) AF: 0.0000431 AC: 1 AN: 23200

East Asian (EAS) AF: 0.0000294 AC: 1 AN: 33966

South Asian (SAS) AF: 0.0000141 AC: 1 AN: 70770

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48682

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5222

European-Non Finnish (NFE) AF: 0.0000263 AC: 28 AN: 1063834

Other (OTH) AF: 0.0000357 AC: 2 AN: 55954

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.0000808 AC: 2

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	-	-	CPLANE1-related disorder (1)
1	-	-	Joubert syndrome 17 (2)
1	-	-	not provided (1)
-	1	-	Orofaciodigital syndrome type 6;C3553264:Joubert syndrome 17 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.21	T
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.91	D
M_CAP	Uncertain	0.14	D
MetaRNN	Uncertain	0.74	D
MetaSVM	Benign	-0.76	T
PhyloP100		5.1
PROVEAN	Pathogenic	-4.5	D
REVEL	Uncertain	0.39
Sift	Uncertain	0.0020	D
Sift4G	Pathogenic	0.0010	D
Vest4		0.86
MutPred		0.55		Loss of MoRF binding (P = 0.0755)
MVP		0.54
MPC		0.67
ClinPred		0.82	D
GERP RS		5.6
Varity_R		0.32
gMVP		0.41
Mutation Taster		=8/92	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs760906097; hg19: chr5-37221561;