12-94308911-GT-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_Moderate PM2 PP5_Very_Strong

The NM_016122.3(CEP83):c.2007del(p.Glu669AspfsTer14) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000872 in 1,606,224 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: CEP83 NM_016122.3 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 0.158

Genes affected

CEP83 (HGNC:17966): (centrosomal protein 83) The protein encoded by this gene is a centriolar protein involved in primary cilium assembly. Defects in this gene have been associated with infantile nephronophthisis and intellectual disability. [provided by RefSeq, Oct 2016]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.047 CDS is truncated, and there are 1 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 12-94308911-GT-G is Pathogenic according to our data. Variant chr12-94308911-GT-G is described in ClinVar as [Pathogenic]. Clinvar id is 1070747.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-94308911-GT-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CEP83	NM_016122.3	c.2007del	p.Glu669AspfsTer14	frameshift_variant	17/17	ENST00000397809.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CEP83	ENST00000397809.10	c.2007del	p.Glu669AspfsTer14	frameshift_variant	17/17	1	NM_016122.3	P1
CEP83	ENST00000339839.9	c.2007del	p.Glu669AspfsTer14	frameshift_variant	16/16	1		P1
CEP83	ENST00000552632.5	c.399del	p.Glu133AspfsTer14	frameshift_variant	4/5	3
CEP83	ENST00000546783.1	n.461del		non_coding_transcript_exon_variant	3/3	3

Frequencies

GnomAD3 genomes AF: 0.0000657 AC: 10 AN: 152128 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000459

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: 0.00

Gnomad OTH AF: 0.000478

GnomAD4 exome AF: 0.00000275 AC: 4 AN: 1454096 Hom.: 0 Cov.: 27 AF XY: 0.00000414 AC XY: 3 AN XY: 723920

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000448

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000333

GnomAD4 genome AF: 0.0000657 AC: 10 AN: 152128 Hom.: 0 Cov.: 32 AF XY: 0.0000673 AC XY: 5 AN XY: 74298

Gnomad4 AFR AF: 0.0000483

Gnomad4 AMR AF: 0.000459

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.000106

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Sep 04, 2023

Frameshift variant predicted to result in protein truncation as the last 33 amino acids are replaced with 13 different amino acids, although loss-of-function variants have not been reported downstream of this position in the protein; Published functional studies demonstrate a damaging effect on centrosome localization and interactions with its binding partner, CEP164 (Failler et al., 2014); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 24882706, 30655312) -

Nephronophthisis 18 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Apr 06, 2023

For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the CEP83 protein in which other variant(s) (p.Gln692del) have been observed in individuals with CEP83-related conditions (PMID: 24882706). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. Experimental studies have shown that this premature translational stop signal affects CEP83 function (PMID: 24882706). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. ClinVar contains an entry for this variant (Variation ID: 1070747). This premature translational stop signal has been observed in individuals with nephronophthisis (PMID: 24882706, 30655312). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Glu669Aspfs*14) in the CEP83 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 33 amino acid(s) of the CEP83 protein. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs922686745; hg19: chr12-94702687;