Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBA1

The NM_014956.5(CEP164):c.281G>A(p.Ser94Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.203 in 1,613,052 control chromosomes in the GnomAD database, including 34,334 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. S94S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.22 ( 3700 hom., cov: 30)

Exomes 𝑓: 0.20 ( 30634 hom. )

Consequence

CEP164
NM_014956.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 0.937

Publications

34 publications found

Variant links:

Genes affected

CEP164 (HGNC:29182): (centrosomal protein 164) This gene encodes a centrosomal protein involved in microtubule organization, DNA damage response, and chromosome segregation. The encoded protein is required for assembly of primary cilia and localizes to mature centrioles. Defects in this gene are a cause of nephronophthisis-related ciliopathies. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2012]

CEP164 Gene-Disease associations (from GenCC):

ciliopathy
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
nephronophthisis 15
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, Ambry Genetics, G2P
Senior-Loken syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

CEP164 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -18 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_014956.5

BP4

Computational evidence support a benign effect (MetaRNN=0.0023169518).

BP6

Variant 11-117351876-G-A is Benign according to our data. Variant chr11-117351876-G-A is described in ClinVar as Benign. ClinVar VariationId is 260481.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.269 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014956.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CEP164	NM_014956.5	MANE Select	c.281G>A	p.Ser94Asn	missense	Exon 5 of 33	NP_055771.4
CEP164	NM_001440949.1		c.281G>A	p.Ser94Asn	missense	Exon 5 of 33	NP_001427878.1
CEP164	NM_001440950.1		c.281G>A	p.Ser94Asn	missense	Exon 5 of 33	NP_001427879.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CEP164	ENST00000278935.8	TSL:1 MANE Select	c.281G>A	p.Ser94Asn	missense	Exon 5 of 33	ENSP00000278935.3
CEP164	ENST00000533570.1	TSL:1	c.281G>A	p.Ser94Asn	missense	Exon 4 of 4	ENSP00000431302.1
CEP164	ENST00000527609.5	TSL:1	c.281G>A	p.Ser94Asn	missense	Exon 5 of 5	ENSP00000436351.2

Frequencies

GnomAD3 genomes

AF:

0.216

AC:

32711

AN:

151178

Hom.:

3690

Cov.:

show subpopulations

Gnomad AFR

AF:

0.273

Gnomad AMI

AF:

0.314

Gnomad AMR

AF:

0.257

Gnomad ASJ

AF:

0.235

Gnomad EAS

AF:

0.136

Gnomad SAS

AF:

0.233

Gnomad FIN

AF:

0.139

Gnomad MID

AF:

0.226

Gnomad NFE

AF:

0.188

Gnomad OTH

AF:

0.211

GnomAD2 exomes

AF:

0.211

AC:

53130

AN:

251368

AF XY:

0.209

show subpopulations

Gnomad AFR exome

AF:

0.271

Gnomad AMR exome

AF:

0.298

Gnomad ASJ exome

AF:

0.245

Gnomad EAS exome

AF:

0.136

Gnomad FIN exome

AF:

0.140

Gnomad NFE exome

AF:

0.190

Gnomad OTH exome

AF:

0.221

GnomAD4 exome

AF:

0.201

AC:

294485

AN:

1461762

Hom.:

30634

Cov.:

AF XY:

0.202

AC XY:

146847

AN XY:

727188

show subpopulations

African (AFR)

AF:

0.275

AC:

9191

AN:

33476

American (AMR)

AF:

0.293

AC:

13094

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.247

AC:

6448

AN:

26132

East Asian (EAS)

AF:

0.125

AC:

4974

AN:

39700

South Asian (SAS)

AF:

0.244

AC:

21057

AN:

86248

European-Finnish (FIN)

AF:

0.145

AC:

7731

AN:

53418

Middle Eastern (MID)

AF:

0.257

AC:

1485

AN:

5768

European-Non Finnish (NFE)

AF:

0.196

AC:

217906

AN:

1111912

Other (OTH)

AF:

0.209

AC:

12599

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

13184

26368

39552

52736

65920

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

7804

15608

23412

31216

39020

<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:

0.216

AC:

32754

AN:

151290

Hom.:

3700

Cov.:

AF XY:

0.213

AC XY:

15735

AN XY:

73882

show subpopulations

African (AFR)

AF:

0.273

AC:

11242

AN:

41188

American (AMR)

AF:

0.257

AC:

3904

AN:

15190

Ashkenazi Jewish (ASJ)

AF:

0.235

AC:

816

AN:

3472

East Asian (EAS)

AF:

0.136

AC:

702

AN:

5144

South Asian (SAS)

AF:

0.234

AC:

1121

AN:

4798

European-Finnish (FIN)

AF:

0.139

AC:

1440

AN:

10328

Middle Eastern (MID)

AF:

0.219

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.188

AC:

12740

AN:

67866

Other (OTH)

AF:

0.209

AC:

439

AN:

2102

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1239

2478

3718

4957

6196

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

348

696

1044

1392

1740

<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:

0.203

Hom.:

11060

Bravo

AF:

0.229

TwinsUK

AF:

0.203

AC:

753

ALSPAC

AF:

0.188

AC:

724

ESP6500AA

AF:

0.275

AC:

1211

ESP6500EA

AF:

0.200

AC:

1718

ExAC

AF:

0.209

AC:

25382

Asia WGS

AF:

0.193

AC:

673

AN:

3478

EpiCase

AF:

0.189

EpiControl

AF:

0.190

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (3)

Nephronophthisis 15 (2)

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.048

BayesDel_addAF

Benign

-0.62

BayesDel_noAF

Benign

-0.51

CADD

Benign

7.5

(source)

DANN

Benign

0.51

DEOGEN2

Benign

0.0048

Eigen

Benign

-1.1

Eigen_PC

Benign

-0.81

FATHMM_MKL

Benign

0.068

LIST_S2

Benign

0.045

MetaRNN

Benign

0.0023

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-2.5

PhyloP100

0.94

PrimateAI

Benign

0.32

PROVEAN

Benign

1.2

REVEL

Benign

0.12

Sift

Benign

0.80

Sift4G

Benign

0.73

Polyphen

0.0

Vest4

0.044

MPC

0.095

ClinPred

0.0042

GERP RS

3.7

PromoterAI

0.039

Neutral

(source)

Varity_R

0.033

gMVP

0.046

Mutation Taster

=98/2

polymorphism (auto)

(source)

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

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rs490262

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over