rs587777487

Positions:

• chr12-94333527-C-A
• chr12-94333527-C-G
• chr12-94333527-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM2 PM5 BP4

The ENST00000397809.10(CEP83):​c.1532G>T​(p.Arg511Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R511Q) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CEP83 ENST00000397809.10 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.37

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr12-94333527-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 139544.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.2731048).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CEP83	NM_016122.3	c.1532G>T	p.Arg511Leu	missense_variant	13/17	ENST00000397809.10	NP_057206.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CEP83	ENST00000397809.10	c.1532G>T	p.Arg511Leu	missense_variant	13/17	1	NM_016122.3	ENSP00000380911	P1
CEP83	ENST00000339839.9	c.1532G>T	p.Arg511Leu	missense_variant	12/16	1		ENSP00000344655	P1
CEP83	ENST00000547232.5	c.1433G>T	p.Arg478Leu	missense_variant, NMD_transcript_variant	13/17	1		ENSP00000447783
CEP83	ENST00000546587.1	n.408G>T		non_coding_transcript_exon_variant	2/3	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

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

Aug 23, 2022

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 the p.Arg511 amino acid residue in CEP83. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 24882706). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Not Available"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Not Available"). ClinVar contains an entry for this variant (Variation ID: 1389963). This variant has not been reported in the literature in individuals affected with CEP83-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 511 of the CEP83 protein (p.Arg511Leu). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.015	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.053	.;.;T
Eigen	Benign	0.19
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.89	.;D;D
M_CAP	Benign	0.082	D
MetaRNN	Benign	0.27	T;T;T
MetaSVM	Benign	-0.73	T
MutationTaster	Benign	0.94	D;D;D
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-2.0	N;N;.
REVEL	Benign	0.19
Sift	Benign	0.059	T;T;.
Sift4G	Benign	0.17	T;T;D
Vest4		0.41
MVP		0.38
MPC		0.37
ClinPred		0.80	D
GERP RS		5.0
Varity_R		0.19
gMVP		0.31

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-94727303;