rs149313666

Variant names:

• chr5-37182760-C-T
• rs149313666
• NM_001384732.1:c.5421G>A

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Moderate BP6 BS1 BS2

The NM_001384732.1(CPLANE1):​c.5421G>A​(p.Lys1807Lys) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00638 in 1,582,064 control chromosomes in the GnomAD database, including 62 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0052 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0065 (60 hom.)
• Consequence: CPLANE1 NM_001384732.1 splice_region, synonymous
• Scores: Splicing: ADA: 0.2161
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:10
• Conservation: PhyloP100: 2.83
• Publications: 6 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: Benign. The variant received -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.39).
• BP6: Variant 5-37182760-C-T is Benign according to our data. Variant chr5-37182760-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 158041.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00525 (798/152054) while in subpopulation SAS AF = 0.0129 (62/4806). AF 95% confidence interval is 0.0103. There are 2 homozygotes in GnomAd4. There are 405 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

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.5421G>A	p.Lys1807Lys	splice_region synonymous	Exon 26 of 53	NP_001371661.1	A0A494BZW6
	CPLANE1	NM_023073.4		c.5421G>A	p.Lys1807Lys	splice_region synonymous	Exon 26 of 52	NP_075561.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CPLANE1	ENST00000651892.2	MANE Select	c.5421G>A	p.Lys1807Lys	splice_region synonymous	Exon 26 of 53	ENSP00000498265.2	A0A494BZW6
	CPLANE1	ENST00000514429.5	TSL:1	c.2565G>A	p.Lys855Lys	splice_region synonymous	Exon 11 of 37	ENSP00000424223.1	H0Y9I8
	CPLANE1	ENST00000509849.5	TSL:1	n.2436G>A		splice_region non_coding_transcript_exon	Exon 11 of 37	ENSP00000426337.1	H0YA77

Frequencies

GnomAD3 genomes AF: 0.00524 AC: 796 AN: 151938 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000774

Gnomad AMI AF: 0.0340

Gnomad AMR AF: 0.00360

Gnomad ASJ AF: 0.0219

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0127

Gnomad FIN AF: 0.00474

Gnomad MID AF: 0.0159

Gnomad NFE AF: 0.00690

Gnomad OTH AF: 0.00815

GnomAD2 exomes AF: 0.00697 AC: 1679 AN: 240888 AF XY: 0.00743

Gnomad AFR exome AF: 0.000440

Gnomad AMR exome AF: 0.00368

Gnomad ASJ exome AF: 0.0189

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00538

Gnomad NFE exome AF: 0.00774

Gnomad OTH exome AF: 0.00528

GnomAD4 exome AF: 0.00650 AC: 9301 AN: 1430010 Hom.: 60 Cov.: 28 AF XY: 0.00677 AC XY: 4827 AN XY: 712692

African (AFR) AF: 0.000860 AC: 28 AN: 32562

American (AMR) AF: 0.00377 AC: 160 AN: 42404

Ashkenazi Jewish (ASJ) AF: 0.0194 AC: 498 AN: 25628

East Asian (EAS) AF: 0.00 AC: 0 AN: 39420

South Asian (SAS) AF: 0.0139 AC: 1168 AN: 83734

European-Finnish (FIN) AF: 0.00513 AC: 268 AN: 52282

Middle Eastern (MID) AF: 0.0162 AC: 92 AN: 5672

European-Non Finnish (NFE) AF: 0.00612 AC: 6661 AN: 1089026

Other (OTH) AF: 0.00719 AC: 426 AN: 59282

GnomAD4 genome AF: 0.00525 AC: 798 AN: 152054 Hom.: 2 Cov.: 32 AF XY: 0.00545 AC XY: 405 AN XY: 74338

African (AFR) AF: 0.000771 AC: 32 AN: 41486

American (AMR) AF: 0.00360 AC: 55 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0219 AC: 76 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.0129 AC: 62 AN: 4806

European-Finnish (FIN) AF: 0.00474 AC: 50 AN: 10550

Middle Eastern (MID) AF: 0.0205 AC: 6 AN: 292

European-Non Finnish (NFE) AF: 0.00691 AC: 470 AN: 67972

Other (OTH) AF: 0.00759 AC: 16 AN: 2108

Alfa AF: 0.00662 Hom.: 7

Bravo AF: 0.00527

Asia WGS AF: 0.00635 AC: 22 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	4	not specified (4)
-	1	2	Joubert syndrome 17 (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.39
CADD	Benign	12
DANN	Benign	0.75
PhyloP100		2.8
Mutation Taster		=32/68	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.22
dbscSNV1_RF	Benign	0.51
SpliceAI score (max)		0.25		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.25		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs149313666; hg19: chr5-37182862; COSMIC: COSV57054815;