rs145520487

Variant names:

• chr5-37187826-A-G
• rs145520487
• NM_001384732.1:c.3828T>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_001384732.1(CPLANE1):​c.3828T>C​(p.Leu1276Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000922 in 1,613,030 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00082 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00093 (3 hom.)
• Consequence: CPLANE1 NM_001384732.1 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2 B:6
• Conservation: PhyloP100: -0.950
• 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: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.67).
• BP6: Variant 5-37187826-A-G is Benign according to our data. Variant chr5-37187826-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 195696.
• BP7: Synonymous conserved (PhyloP=-0.95 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000821 (125/152340) while in subpopulation AMR AF = 0.00235 (36/15308). AF 95% confidence interval is 0.00175. There are 0 homozygotes in GnomAd4. There are 72 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 3 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.3828T>C	p.Leu1276Leu	synonymous	Exon 22 of 53	NP_001371661.1	A0A494BZW6
	CPLANE1	NM_023073.4		c.3828T>C	p.Leu1276Leu	synonymous	Exon 22 of 52	NP_075561.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CPLANE1	ENST00000651892.2	MANE Select	c.3828T>C	p.Leu1276Leu	synonymous	Exon 22 of 53	ENSP00000498265.2	A0A494BZW6
	CPLANE1	ENST00000514429.5	TSL:1	c.972T>C	p.Leu324Leu	synonymous	Exon 7 of 37	ENSP00000424223.1	H0Y9I8
	CPLANE1	ENST00000509849.5	TSL:1	n.843T>C		non_coding_transcript_exon	Exon 7 of 37	ENSP00000426337.1	H0YA77

Frequencies

GnomAD3 genomes AF: 0.000821 AC: 125 AN: 152222 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00235

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: 0.00110

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.000655 AC: 164 AN: 250548 AF XY: 0.000605

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.00207

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000741

Gnomad OTH exome AF: 0.000817

GnomAD4 exome AF: 0.000933 AC: 1363 AN: 1460690 Hom.: 3 Cov.: 30 AF XY: 0.000867 AC XY: 630 AN XY: 726630

African (AFR) AF: 0.000419 AC: 14 AN: 33444

American (AMR) AF: 0.00186 AC: 83 AN: 44624

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26102

East Asian (EAS) AF: 0.00 AC: 0 AN: 39636

South Asian (SAS) AF: 0.0000465 AC: 4 AN: 86056

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53386

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5762

European-Non Finnish (NFE) AF: 0.00109 AC: 1211 AN: 1111326

Other (OTH) AF: 0.000812 AC: 49 AN: 60354

GnomAD4 genome AF: 0.000821 AC: 125 AN: 152340 Hom.: 0 Cov.: 32 AF XY: 0.000966 AC XY: 72 AN XY: 74500

African (AFR) AF: 0.000216 AC: 9 AN: 41580

American (AMR) AF: 0.00235 AC: 36 AN: 15308

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00110 AC: 75 AN: 68026

Other (OTH) AF: 0.00237 AC: 5 AN: 2114

Alfa AF: 0.000870 Hom.: 0

Bravo AF: 0.000941

EpiCase AF: 0.000328

EpiControl AF: 0.000593

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	5.3
DANN	Benign	0.72
PhyloP100		-0.95
Mutation Taster		=100/0	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: rs145520487; hg19: chr5-37187928;