NM_016122.3:c.1565T>G

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. L522L) has been classified as Likely benign.

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

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

nephronophthisis 18
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp, G2P
nephronophthisis 2
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

CEP83 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

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 VariationId is 541796.

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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CEP83	NM_016122.3 link	c.1565T>G	p.Leu522Arg	missense_variant	Exon 13 of 17	ENST00000397809.10	NP_057206.2	Q9Y592-1Q3B787

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CEP83	ENST00000397809.10 link	c.1565T>G	p.Leu522Arg	missense_variant	Exon 13 of 17	1	NM_016122.3	ENSP00000380911.4	Q9Y592-1
CEP83	ENST00000339839.9 link	c.1565T>G	p.Leu522Arg	missense_variant	Exon 12 of 16	1		ENSP00000344655.5	Q9Y592-1
CEP83	ENST00000547232.5 link	n.1466T>G		non_coding_transcript_exon_variant	Exon 13 of 17	1		ENSP00000447783.1	A0A338VFC5
CEP83	ENST00000546587.1 link	n.441T>G		non_coding_transcript_exon_variant	Exon 2 of 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

GnomAD2 exomes

AF:

0.000342

AC:

AN:

248758

AF XY:

0.000245

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 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

African (AFR)

AF:

0.00524

AC:

175

AN:

33412

American (AMR)

AF:

0.000269

AC:

AN:

44574

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26124

East Asian (EAS)

AF:

0.00

AC:

AN:

39664

South Asian (SAS)

AF:

0.0000116

AC:

AN:

85964

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53382

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1111646

Other (OTH)

AF:

0.000199

AC:

AN:

60364

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00120

AC:

182

AN:

152278

Hom.:

Cov.:

AF XY:

0.00124

AC XY:

AN XY:

74472

show subpopulations

African (AFR)

AF:

0.00431

AC:

179

AN:

41564

American (AMR)

AF:

0.000131

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68000

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000591

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

Feb 14, 2024

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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 -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

CEP83-related disorder

Benign:1

Mar 16, 2021

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

Dec 15, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

(source)

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

PhyloP100

2.0

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

Mutation Taster

=81/19

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over