rs74478954

Positions:

• chr5-37195874-A-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_001384732.1(CPLANE1):​c.3795T>A​(p.Val1265=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00564 in 1,610,988 control chromosomes in the GnomAD database, including 116 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.016 (49 hom., cov: 32)
  • Exomes 𝑓: 0.0046 (67 hom.)
• Consequence: CPLANE1 NM_001384732.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.01

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 -16 ACMG points.

• BP6: Variant 5-37195874-A-T is Benign according to our data. Variant chr5-37195874-A-T is described in ClinVar as [Benign]. Clinvar id is 158033.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-37195874-A-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0155 (2366/152236) while in subpopulation AFR AF= 0.0469 (1948/41530). AF 95% confidence interval is 0.0452. There are 49 homozygotes in gnomad4. There are 1135 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 49 Mitochondrial gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CPLANE1	NM_001384732.1	c.3795T>A	p.Val1265=	synonymous_variant	21/53	ENST00000651892.2	NP_001371661.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CPLANE1	ENST00000651892.2	c.3795T>A	p.Val1265=	synonymous_variant	21/53		NM_001384732.1	ENSP00000498265	A2

Frequencies

GnomAD3 genomes AF: 0.0155 AC: 2362 AN: 152118 Hom.: 49 Cov.: 32

Gnomad AFR AF: 0.0469

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00694

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0101

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.00331

Gnomad OTH AF: 0.0134

GnomAD3 exomes AF: 0.00685 AC: 1700 AN: 248134 Hom.: 29 AF XY: 0.00663 AC XY: 890 AN XY: 134182

Gnomad AFR exome AF: 0.0485

Gnomad AMR exome AF: 0.00504

Gnomad ASJ exome AF: 0.000501

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00887

Gnomad FIN exome AF: 0.0000926

Gnomad NFE exome AF: 0.00393

Gnomad OTH exome AF: 0.00548

GnomAD4 exome AF: 0.00461 AC: 6720 AN: 1458752 Hom.: 67 Cov.: 30 AF XY: 0.00482 AC XY: 3495 AN XY: 725652

Gnomad4 AFR exome AF: 0.0502

Gnomad4 AMR exome AF: 0.00542

Gnomad4 ASJ exome AF: 0.000423

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.0101

Gnomad4 FIN exome AF: 0.000131

Gnomad4 NFE exome AF: 0.00306

Gnomad4 OTH exome AF: 0.00664

GnomAD4 genome AF: 0.0155 AC: 2366 AN: 152236 Hom.: 49 Cov.: 32 AF XY: 0.0152 AC XY: 1135 AN XY: 74446

Gnomad4 AFR AF: 0.0469

Gnomad4 AMR AF: 0.00693

Gnomad4 ASJ AF: 0.000865

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00995

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.00331

Gnomad4 OTH AF: 0.0132

Alfa AF: 0.00646 Hom.: 1

Bravo AF: 0.0177

Asia WGS AF: 0.00289 AC: 10 AN: 3476

EpiCase AF: 0.00369

EpiControl AF: 0.00645

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 23, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Joubert syndrome 17 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	5.2
DANN	Benign	0.80

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.25		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.25		Position offset: 3

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

Publications

LitVar

Other links and lift over

dbSNP: rs74478954; hg19: chr5-37195976;