5-37221459-G-T

Variant names:

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

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1 PM2 PM5

The NM_001384732.1(CPLANE1):​c.2611C>A​(p.Arg871Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. 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: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CPLANE1 NM_001384732.1 missense
• Clinical Significance: Not reported in ClinVar
• 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: Likely_pathogenic. The variant received 6 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.

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>A	p.Arg871Ser	missense	Exon 15 of 53	NP_001371661.1
	CPLANE1	NM_023073.4		c.2611C>A	p.Arg871Ser	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>A	p.Arg871Ser	missense	Exon 15 of 53	ENSP00000498265.2
	CPLANE1	ENST00000508244.5	TSL:5	c.2611C>A	p.Arg871Ser	missense	Exon 14 of 51	ENSP00000421690.1
	CPLANE1	ENST00000425232.7	TSL:5	n.*1940C>A		non_coding_transcript_exon	Exon 12 of 30	ENSP00000389014.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1353708 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 667016

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

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

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23200

East Asian (EAS) AF: 0.00 AC: 0 AN: 33966

South Asian (SAS) AF: 0.00 AC: 0 AN: 70772

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: 0.00 AC: 0 AN: 1063838

Other (OTH) AF: 0.00 AC: 0 AN: 55954

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Uncertain	0.078	D
BayesDel_noAF	Benign	-0.13
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.29	T
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.073	D
MetaRNN	Uncertain	0.72	D
MetaSVM	Benign	-0.89	T
PhyloP100		5.1
PROVEAN	Uncertain	-2.9	D
REVEL	Benign	0.24
Sift	Uncertain	0.011	D
Sift4G	Uncertain	0.0060	D
Vest4		0.65
MutPred		0.49		Gain of sheet (P = 0.0477)
MVP		0.50
MPC		0.61
ClinPred		0.99	D
GERP RS		5.6
Varity_R		0.39
gMVP		0.48
Mutation Taster		=18/82	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.17		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;