Variant 4-55953263-C-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_025009.5(CEP135):c.292C>A(p.Gln98Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000289 in 1,386,256 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 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: 0.0000029 ( 0 hom. )

Consequence

CEP135
NM_025009.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.85

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 links:

LOC124900705 (HGNC:):

LOC124900705 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.036207855).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
CEP135	NM_025009.5 linkuse as main transcript	c.292C>A	p.Gln98Lys	missense_variant	3/26	ENST00000257287.5
LOC124900705	XR_007058124.1 linkuse as main transcript	n.198-792G>T		intron_variant, non_coding_transcript_variant
CEP135	XM_006714055.4 linkuse as main transcript	c.292C>A	p.Gln98Lys	missense_variant	3/26

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CEP135	ENST00000257287.5 linkuse as main transcript	c.292C>A	p.Gln98Lys	missense_variant	3/26	1	NM_025009.5	P1	Q66GS9-1
CEP135	ENST00000422247.6 linkuse as main transcript	c.292C>A	p.Gln98Lys	missense_variant	3/6	2			Q66GS9-2
CEP135	ENST00000706800.1 linkuse as main transcript	n.465C>A		non_coding_transcript_exon_variant	3/5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000156

AC:

AN:

192266

Hom.:

AF XY:

0.0000190

AC XY:

AN XY:

105402

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000144

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000289

AC:

AN:

1386256

Hom.:

Cov.:

AF XY:

0.00000437

AC XY:

AN XY:

686812

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000532

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 03, 2022

This sequence change replaces glutamine, which is neutral and polar, with lysine, which is basic and polar, at codon 98 of the CEP135 protein (p.Gln98Lys). This variant is present in population databases (rs749547226, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with CEP135-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The lysine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.070

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.66

CADD

Benign

DANN

Benign

0.25

DEOGEN2

Benign

0.0036

.;T

Eigen

Benign

-0.85

Eigen_PC

Benign

-0.75

FATHMM_MKL

Benign

0.58

LIST_S2

Benign

0.67

T;T

M_CAP

Benign

0.0074

MetaRNN

Benign

0.036

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.37

N;N

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.30

PROVEAN

Benign

-0.25

N;N

REVEL

Benign

0.085

Sift

Benign

1.0

T;T

Sift4G

Benign

1.0

T;T

Polyphen

0.0020

B;B

Vest4

0.16

MutPred

0.17

Gain of ubiquitination at Q98 (P = 0.0258);Gain of ubiquitination at Q98 (P = 0.0258);

MVP

0.28

MPC

0.072

ClinPred

0.010

GERP RS

3.3

Varity_R

0.14

gMVP

0.090

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over