chr12-94308843-TTGTTTTCTTTG-T

Position:

• chr12-94308843-TTGTTTTCTTTG-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PVS1_Moderate PM2

The NM_016122.3(CEP83):​c.2065_2075del​(p.Gln689ThrfsTer37) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CEP83 NM_016122.3 frameshift
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.60

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 Uncertain_significance. Variant got 4 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 0.0195 CDS is truncated, and there are 1 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CEP83	NM_016122.3	c.2065_2075del	p.Gln689ThrfsTer37	frameshift_variant	17/17	ENST00000397809.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CEP83	ENST00000397809.10	c.2065_2075del	p.Gln689ThrfsTer37	frameshift_variant	17/17	1	NM_016122.3	P1
CEP83	ENST00000339839.9	c.2065_2075del	p.Gln689ThrfsTer37	frameshift_variant	16/16	1		P1
CEP83	ENST00000552632.5	c.457_467del	p.Gln153ThrfsTer59	frameshift_variant	4/5	3
CEP83	ENST00000546783.1	n.519_529del		non_coding_transcript_exon_variant	3/3	3

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Nephronophthisis 18 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 26, 2020

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant disrupts a region of the protein in which other variant(s) (p.Gln692del) have been observed in individuals with CEP83-related conditions (PMID: 24882706). This suggests that this may be a clinically significant region of the CEP83 protein. This variant has not been reported in the literature in individuals with CEP83-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change results in a frameshift in the CEP83 gene (p.Gln689Thrfs*37). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 13 amino acids of the CEP83 protein and extend the protein by an additional 23 amino acids. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1969370890; hg19: chr12-94702619;