CEP135 p.Glu923Lys

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_025009.5(CEP135):c.2767G>A(p.Glu923Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00189 in 1,576,822 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0016 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0019 ( 2 hom. )

Consequence

CEP135
NM_025009.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: 7.08

Publications

5 publications found

Variant links:

Genes affected

CEP135 (HGNC:29086): (centrosomal protein 135) This gene encodes a centrosomal protein, which acts as a scaffolding protein during early centriole biogenesis, and is also required for centriole-centriole cohesion during interphase. Mutations in this gene are associated with autosomal recessive primary microcephaly-8. [provided by RefSeq, Jun 2012]

CEP135 Gene-Disease associations (from GenCC):

microcephaly 8, primary, autosomal recessive
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
autosomal recessive primary microcephaly
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

CEP135 links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_025009.5, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.01546675).

BP6

Variant 4-56011950-G-A is Benign according to our data. Variant chr4-56011950-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 210679.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00156 (237/152282) while in subpopulation NFE AF = 0.00293 (199/68028). AF 95% confidence interval is 0.00259. There are 0 homozygotes in GnomAd4. There are 113 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_025009.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CEP135	NM_025009.5	MANE Select	c.2767G>A	p.Glu923Lys	missense	Exon 21 of 26	NP_079285.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CEP135	ENST00000257287.5	TSL:1 MANE Select	c.2767G>A	p.Glu923Lys	missense	Exon 21 of 26	ENSP00000257287.3	Q66GS9-1
CEP135	ENST00000506202.1	TSL:1	n.2717G>A		non_coding_transcript_exon	Exon 14 of 19
CEP135	ENST00000916105.1		c.2767G>A	p.Glu923Lys	missense	Exon 21 of 27	ENSP00000586164.1

Frequencies

GnomAD3 genomes

AF:

0.00156

AC:

237

AN:

152164

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000655

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00123

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00292

Gnomad OTH

AF:

0.000957

GnomAD2 exomes

AF:

0.00147

AC:

325

AN:

221644

AF XY:

0.00156

show subpopulations

Gnomad AFR exome

AF:

0.000274

Gnomad AMR exome

AF:

0.000593

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00155

Gnomad NFE exome

AF:

0.00246

Gnomad OTH exome

AF:

0.00173

GnomAD4 exome

AF:

0.00193

AC:

2746

AN:

1424540

Hom.:

Cov.:

AF XY:

0.00195

AC XY:

1383

AN XY:

708092

show subpopulations

African (AFR)

AF:

0.000287

AC:

AN:

31354

American (AMR)

AF:

0.000688

AC:

AN:

37774

Ashkenazi Jewish (ASJ)

AF:

0.000161

AC:

AN:

24858

East Asian (EAS)

AF:

0.00

AC:

AN:

38040

South Asian (SAS)

AF:

0.000390

AC:

AN:

79388

European-Finnish (FIN)

AF:

0.00171

AC:

AN:

52694

Middle Eastern (MID)

AF:

0.000893

AC:

AN:

5598

European-Non Finnish (NFE)

AF:

0.00226

AC:

2482

AN:

1096136

Other (OTH)

AF:

0.00169

AC:

AN:

58698

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

120

239

359

478

598

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

156

234

312

390

<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:

0.00156

AC:

237

AN:

152282

Hom.:

Cov.:

AF XY:

0.00152

AC XY:

113

AN XY:

74466

show subpopulations

African (AFR)

AF:

0.000241

AC:

AN:

41550

American (AMR)

AF:

0.000654

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5190

South Asian (SAS)

AF:

0.000207

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00123

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00293

AC:

199

AN:

68028

Other (OTH)

AF:

0.000947

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

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:

0.00196

Hom.:

Bravo

AF:

0.00149

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

CEP135-related disorder (1)

not provided (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.53

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.30

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.17

Eigen

Pathogenic

0.83

Eigen_PC

Pathogenic

0.82

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.95

M_CAP

Benign

0.043

MetaRNN

Benign

0.015

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.4

PhyloP100

7.1

PrimateAI

Uncertain

0.69

PROVEAN

Uncertain

-3.0

REVEL

Benign

0.22

Sift

Uncertain

0.0030

Sift4G

Uncertain

0.028

Varity_R

0.69

gMVP

0.32

Mutation Taster

=81/19

polymorphism

(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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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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

Computational scores

Splicing

Publications

Other links and lift over