12-94308857-T-G

Position:

• chr12-94308857-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The ENST00000397809.10(CEP83):​c.2062A>C​(p.Thr688Pro) 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. Variant has been reported in ClinVar 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: 2.58

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.32030022).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CEP83	NM_016122.3	c.2062A>C	p.Thr688Pro	missense_variant	17/17	ENST00000397809.10	NP_057206.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CEP83	ENST00000397809.10	c.2062A>C	p.Thr688Pro	missense_variant	17/17	1	NM_016122.3	ENSP00000380911	P1
CEP83	ENST00000339839.9	c.2062A>C	p.Thr688Pro	missense_variant	16/16	1		ENSP00000344655	P1
CEP83	ENST00000552632.5	c.454A>C	p.Thr152Pro	missense_variant	4/5	3		ENSP00000447094
CEP83	ENST00000546783.1	n.516A>C		non_coding_transcript_exon_variant	3/3	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000401 AC: 1 AN: 249164 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135164

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000885

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000828 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Apr 01, 2024

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.69
BayesDel_addAF	Benign	-0.050	T
BayesDel_noAF	Benign	-0.31
CADD	Pathogenic	27
DANN	Uncertain	1.0
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.73	T;.;T
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.32	T;T;T
MetaSVM	Benign	-0.81	T
MutationTaster	Benign	0.97	D;D
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-2.8	D;N;N
REVEL	Benign	0.14
Sift	Uncertain	0.028	D;D;D
Sift4G	Uncertain	0.031	D;T;T
Vest4		0.40
MVP		0.72
MPC		0.50
ClinPred		0.89	D
GERP RS		5.8
Varity_R		0.19
gMVP		0.55

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: rs780830907; hg19: chr12-94702633;