Genetic Variant CEP135:p.Ser622Arg (chr4-55991942-C-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_025009.5(CEP135):c.1866C>G(p.Ser622Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000766 in 1,305,482 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/24 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.7e-7 ( 0 hom. )

Consequence

CEP135
NM_025009.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.695

Publications

0 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:

ENSG00000299857 (HGNC:):

ENSG00000299857 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CEP135	NM_025009.5 link	c.1866C>G	p.Ser622Arg	missense_variant	Exon 15 of 26	ENST00000257287.5	NP_079285.2	Q66GS9-1
CEP135	XM_006714055.4 link	c.1833C>G	p.Ser611Arg	missense_variant	Exon 15 of 26		XP_006714118.1
CEP135	XM_005265788.5 link	c.795C>G	p.Ser265Arg	missense_variant	Exon 8 of 19		XP_005265845.1
CEP135	XM_011534412.2 link	c.336C>G	p.Ser112Arg	missense_variant	Exon 5 of 16		XP_011532714.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CEP135	ENST00000257287.5 link	c.1866C>G	p.Ser622Arg	missense_variant	Exon 15 of 26	1	NM_025009.5	ENSP00000257287.3	Q66GS9-1
CEP135	ENST00000506202.1 link	n.1816C>G		non_coding_transcript_exon_variant	Exon 8 of 19	1
ENSG00000299857	ENST00000766957.1 link	n.107+5510G>C		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.66e-7

AC:

AN:

1305482

Hom.:

Cov.:

AF XY:

0.00000153

AC XY:

AN XY:

652952

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

27554

American (AMR)

AF:

0.00

AC:

AN:

29842

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23368

East Asian (EAS)

AF:

0.00

AC:

AN:

36890

South Asian (SAS)

AF:

0.00

AC:

AN:

72830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52234

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4586

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1003948

Other (OTH)

AF:

0.0000184

AC:

AN:

54230

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jun 27, 2014

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.67

CADD

Benign

0.17

(source)

DANN

Benign

0.84

DEOGEN2

Benign

0.0042

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.016

LIST_S2

Benign

0.53

M_CAP

Benign

0.0066

MetaRNN

Benign

0.036

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.86

PhyloP100

-0.69

PrimateAI

Benign

0.34

PROVEAN

Benign

-0.41

REVEL

Benign

0.062

Sift

Benign

0.61

Sift4G

Benign

0.58

Polyphen

0.0020

Vest4

0.17

MutPred

0.15

Loss of ubiquitination at K624 (P = 0.1);

MVP

0.14

MPC

0.072

ClinPred

0.020

GERP RS

-4.6

Varity_R

0.060

gMVP

0.066

Mutation Taster

=94/6

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.35

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.35

Position offset: -8

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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over