rs143626904

Positions:

• chr5-37138733-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001384732.1(CPLANE1):​c.8779A>G​(p.Met2927Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000307 in 1,610,410 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0018 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00015 (2 hom.)
• Consequence: CPLANE1 NM_001384732.1 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.79

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0030770898).
• BP6: Variant 5-37138733-T-C is Benign according to our data. Variant chr5-37138733-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 197531.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00182 (277/152324) while in subpopulation AFR AF= 0.00632 (263/41584). AF 95% confidence interval is 0.0057. There are 1 homozygotes in gnomad4. There are 141 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CPLANE1	NM_001384732.1	c.8779A>G	p.Met2927Val	missense_variant	46/53	ENST00000651892.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CPLANE1	ENST00000651892.2	c.8779A>G	p.Met2927Val	missense_variant	46/53		NM_001384732.1	A2

Frequencies

GnomAD3 genomes AF: 0.00181 AC: 276 AN: 152206 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00632

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000523

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: 0.0000147

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.000468 AC: 116 AN: 247744 Hom.: 1 AF XY: 0.000434 AC XY: 58 AN XY: 133740

Gnomad AFR exome AF: 0.00617

Gnomad AMR exome AF: 0.000297

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000341

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000887

Gnomad OTH exome AF: 0.000663

GnomAD4 exome AF: 0.000150 AC: 218 AN: 1458086 Hom.: 2 Cov.: 30 AF XY: 0.000152 AC XY: 110 AN XY: 725052

Gnomad4 AFR exome AF: 0.00519

Gnomad4 AMR exome AF: 0.000365

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000589

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.000348

GnomAD4 genome AF: 0.00182 AC: 277 AN: 152324 Hom.: 1 Cov.: 33 AF XY: 0.00189 AC XY: 141 AN XY: 74474

Gnomad4 AFR AF: 0.00632

Gnomad4 AMR AF: 0.000523

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.000315 Hom.: 0

Bravo AF: 0.00209

ESP6500AA AF: 0.00840 AC: 37

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000577 AC: 70

Asia WGS AF: 0.000289 AC: 1 AN: 3476

ClinVar

Significance: Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 15, 2014	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 07, 2023	Variant summary: CPLANE1 c.8617A>G (p.Met2873Val) results in a conservative amino acid change in the encoded protein sequence. Four of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00062 in 279152 control chromosomes, predominantly at a frequency of 0.0063 within the African or African-American subpopulation in the gnomAD database, including 2 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 4 fold of the estimated maximal expected allele frequency for a pathogenic variant in CPLANE1 causing Joubert Syndrome And Related Disorders phenotype (0.0015), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. To our knowledge, no occurrence of c.8617A>G in individuals affected with Joubert Syndrome And Related Disorders and no experimental evidence demonstrating its impact on protein function have been reported. Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as likely benign. -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 02, 2021	- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 25, 2021

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	13
DANN	Benign	0.31
DEOGEN2	Benign	0.0038	T;T;T
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.61
FATHMM_MKL	Benign	0.34	N
M_CAP	Benign	0.0060	T
MetaRNN	Benign	0.0031	T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N;N
PROVEAN	Benign	-0.48	N;N;N
REVEL	Benign	0.023
Sift	Benign	0.52	T;T;T
Sift4G	Uncertain	0.046	D;D;D
Vest4		0.090
MVP		0.18
MPC		0.14
ClinPred		0.0048	T
GERP RS		4.3
Varity_R		0.14
gMVP		0.11

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

Publications

LitVar

Other links and lift over

dbSNP: rs143626904; hg19: chr5-37138835;