Genetic Variant CEP135:p.Ile936Leu (chr4-56017651-A-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_025009.5(CEP135):c.2806A>T(p.Ile936Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000695 in 1,438,898 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I936V) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

CEP135
NM_025009.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.66

Publications

1 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

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.06211084).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CEP135	NM_025009.5 link	c.2806A>T	p.Ile936Leu	missense_variant	Exon 22 of 26	ENST00000257287.5	NP_079285.2	Q66GS9-1
CEP135	XM_006714055.4 link	c.2773A>T	p.Ile925Leu	missense_variant	Exon 22 of 26		XP_006714118.1
CEP135	XM_005265788.5 link	c.1735A>T	p.Ile579Leu	missense_variant	Exon 15 of 19		XP_005265845.1
CEP135	XM_011534412.2 link	c.1276A>T	p.Ile426Leu	missense_variant	Exon 12 of 16		XP_011532714.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CEP135	ENST00000257287.5 link	c.2806A>T	p.Ile936Leu	missense_variant	Exon 22 of 26	1	NM_025009.5	ENSP00000257287.3	Q66GS9-1
CEP135	ENST00000506202.1 link	n.2756A>T		non_coding_transcript_exon_variant	Exon 15 of 19	1
CEP135	ENST00000706801.1 link	n.871A>T		non_coding_transcript_exon_variant	Exon 6 of 10

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.95e-7

AC:

AN:

1438898

Hom.:

Cov.:

AF XY:

0.00000140

AC XY:

AN XY:

714068

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32462

American (AMR)

AF:

0.00

AC:

AN:

40956

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25354

East Asian (EAS)

AF:

0.00

AC:

AN:

39148

South Asian (SAS)

AF:

0.00

AC:

AN:

81302

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53070

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5070

European-Non Finnish (NFE)

AF:

9.07e-7

AC:

AN:

1102198

Other (OTH)

AF:

0.00

AC:

AN:

59338

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.085

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.62

CADD

Benign

(source)

DANN

Benign

0.55

DEOGEN2

Benign

0.0049

Eigen

Benign

-0.51

Eigen_PC

Benign

-0.34

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.58

M_CAP

Benign

0.0037

MetaRNN

Benign

0.062

MetaSVM

Benign

-0.98

MutationAssessor

Benign

1.0

PhyloP100

4.7

PrimateAI

Benign

0.44

PROVEAN

Benign

0.21

REVEL

Benign

0.056

Sift

Benign

1.0

Sift4G

Benign

0.56

Polyphen

0.0020

Vest4

0.29

MutPred

0.21

Loss of catalytic residue at I936 (P = 0.3464);

MVP

0.23

MPC

0.058

ClinPred

0.18

GERP RS

1.5

Varity_R

0.050

gMVP

0.092

Mutation Taster

=95/5

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over