rs777686211

Variant names:

• chr5-37226775-TA-T
• rs777686211
• NM_001384732.1:c.1819delT

Your query was ambiguous. Multiple possible variants found:

• chr5-37226775-TA-T
• chr5-37226775-TA-TAA
• chr5-37226775-TA-TAAAAAA

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_001384732.1(CPLANE1):​c.1819delT​(p.Tyr607ThrfsTer6) variant causes a frameshift change. The variant allele was found at a frequency of 0.000178 in 1,539,856 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.00017 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00018 (0 hom.)
• Consequence: CPLANE1 NM_001384732.1 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:23
• Conservation: PhyloP100: 4.24
• Publications: 8 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 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 5-37226775-TA-T is Pathogenic according to our data. Variant chr5-37226775-TA-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 217590.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.1819delT	p.Tyr607ThrfsTer6	frameshift	Exon 12 of 53	NP_001371661.1
	CPLANE1	NM_023073.4		c.1819delT	p.Tyr607ThrfsTer6	frameshift	Exon 12 of 52	NP_075561.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CPLANE1	ENST00000651892.2	MANE Select	c.1819delT	p.Tyr607ThrfsTer6	frameshift	Exon 12 of 53	ENSP00000498265.2
	CPLANE1	ENST00000955438.1		c.1819delT	p.Tyr607ThrfsTer6	frameshift	Exon 12 of 53	ENSP00000625497.1
	CPLANE1	ENST00000508244.5	TSL:5	c.1819delT	p.Tyr607ThrfsTer6	frameshift	Exon 11 of 51	ENSP00000421690.1

Frequencies

GnomAD3 genomes AF: 0.000171 AC: 26 AN: 152060 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000944

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000324

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000161 AC: 23 AN: 142536 AF XY: 0.000226

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000236

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000975

Gnomad FIN exome AF: 0.000123

Gnomad NFE exome AF: 0.000231

Gnomad OTH exome AF: 0.000253

GnomAD4 exome AF: 0.000179 AC: 248 AN: 1387796 Hom.: 0 Cov.: 32 AF XY: 0.000196 AC XY: 134 AN XY: 683914

African (AFR) AF: 0.0000974 AC: 3 AN: 30806

American (AMR) AF: 0.000211 AC: 7 AN: 33226

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24708

East Asian (EAS) AF: 0.00 AC: 0 AN: 35590

South Asian (SAS) AF: 0.0000130 AC: 1 AN: 76718

European-Finnish (FIN) AF: 0.000285 AC: 14 AN: 49062

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5622

European-Non Finnish (NFE) AF: 0.000198 AC: 213 AN: 1074600

Other (OTH) AF: 0.000174 AC: 10 AN: 57464

GnomAD4 genome AF: 0.000171 AC: 26 AN: 152060 Hom.: 0 Cov.: 32 AF XY: 0.000135 AC XY: 10 AN XY: 74304

African (AFR) AF: 0.0000483 AC: 2 AN: 41418

American (AMR) AF: 0.0000655 AC: 1 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.0000944 AC: 1 AN: 10598

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

European-Non Finnish (NFE) AF: 0.000324 AC: 22 AN: 67990

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.000145 Hom.: 0

Bravo AF: 0.000193

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
8	-	-	Joubert syndrome 17 (8)
7	-	-	not provided (7)
3	-	-	Orofaciodigital syndrome type 6;C3553264:Joubert syndrome 17 (3)
1	-	-	CPLANE1-related disorder (1)
1	-	-	Inborn genetic diseases (1)
1	-	-	Jaundice;C0557874:Global developmental delay (1)
1	-	-	Nephronophthisis (1)
1	-	-	Orofaciodigital syndrome type 6 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		4.2
Mutation Taster		=0/200	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: rs777686211; hg19: chr5-37226877; COSMIC: COSV57058698;