12-94333494-A-C

Position:

chr12-94333494-A-C

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM2BP4_StrongBP6BS1

The NM_016122.3(CEP83):c.1565T>G(p.Leu522Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000238 in 1,613,174 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0012 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00014 ( 1 hom. )

Consequence

CEP83
NM_016122.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:3

Conservation

PhyloP100: 2.00

Variant links:

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]

CEP83 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.007227689).

BP6

Variant 12-94333494-A-C is Benign according to our data. Variant chr12-94333494-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 541796.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0012 (182/152278) while in subpopulation AFR AF= 0.00431 (179/41564). AF 95% confidence interval is 0.00379. There are 0 homozygotes in gnomad4. There are 92 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CEP83	NM_016122.3 linkuse as main transcript	c.1565T>G	p.Leu522Arg	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 linkuse as main transcript	c.1565T>G	p.Leu522Arg	missense_variant	13/17	1	NM_016122.3	ENSP00000380911	P1	Q9Y592-1
CEP83	ENST00000339839.9 linkuse as main transcript	c.1565T>G	p.Leu522Arg	missense_variant	12/16	1		ENSP00000344655	P1	Q9Y592-1
CEP83	ENST00000547232.5 linkuse as main transcript	c.1466T>G	p.Leu489Arg	missense_variant, NMD_transcript_variant	13/17	1		ENSP00000447783
CEP83	ENST00000546587.1 linkuse as main transcript	n.441T>G		non_coding_transcript_exon_variant	2/3	3

Frequencies

GnomAD3 genomes

AF:

0.00119

AC:

181

AN:

152160

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00430

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000342

AC:

AN:

248758

Hom.:

AF XY:

0.000245

AC XY:

AN XY:

134950

show subpopulations

Gnomad AFR exome

AF:

0.00524

Gnomad AMR exome

AF:

0.0000582

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:

0.00

Gnomad OTH exome

AF:

0.000332

GnomAD4 exome

AF:

0.000138

AC:

202

AN:

1460896

Hom.:

Cov.:

AF XY:

0.000111

AC XY:

AN XY:

726696

show subpopulations

Gnomad4 AFR exome

AF:

0.00524

Gnomad4 AMR exome

AF:

0.000269

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.000199

GnomAD4 genome

AF:

0.00120

AC:

182

AN:

152278

Hom.:

Cov.:

AF XY:

0.00124

AC XY:

AN XY:

74472

show subpopulations

Gnomad4 AFR

AF:

0.00431

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000247

Hom.:

Bravo

AF:

0.00144

ESP6500AA

AF:

0.00712

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000464

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Feb 14, 2024	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

CEP83-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 16, 2021

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Nephronophthisis 18

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.083

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.53

CADD

Benign

DANN

Benign

0.23

DEOGEN2

Benign

0.021

.;.;T

Eigen

Benign

-0.49

Eigen_PC

Benign

-0.41

FATHMM_MKL

Uncertain

0.76

LIST_S2

Benign

0.69

.;T;T

M_CAP

Benign

0.0076

MetaRNN

Benign

0.0072

T;T;T

MetaSVM

Benign

-1.0

MutationTaster

Benign

0.89

N;N;N

PrimateAI

Benign

0.41

PROVEAN

Benign

-0.040

N;N;.

REVEL

Benign

0.043

Sift

Benign

0.82

T;T;.

Sift4G

Benign

0.74

T;T;T

Vest4

0.43

MVP

0.27

MPC

0.12

ClinPred

0.0052

GERP RS

3.5

Varity_R

0.14

gMVP

0.18

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over