4-55952194-C-T

Position:

chr4-55952194-C-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM2BP4_StrongBP6BS1

The NM_025009.5(CEP135):c.64C>T(p.Arg22Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0002 in 1,613,150 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R22H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0010 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00012 ( 0 hom. )

Consequence

CEP135
NM_025009.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 3.03

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.01755485).

BP6

Variant 4-55952194-C-T is Benign according to our data. Variant chr4-55952194-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 726147.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00101 (153/152196) while in subpopulation AFR AF= 0.00335 (139/41522). AF 95% confidence interval is 0.00289. There are 0 homozygotes in gnomad4. There are 74 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CEP135	NM_025009.5 linkuse as main transcript	c.64C>T	p.Arg22Cys	missense_variant	2/26	ENST00000257287.5
CEP135	XM_006714055.4 linkuse as main transcript	c.64C>T	p.Arg22Cys	missense_variant	2/26

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CEP135	ENST00000257287.5 linkuse as main transcript	c.64C>T	p.Arg22Cys	missense_variant	2/26	1	NM_025009.5	P1	Q66GS9-1
CEP135	ENST00000422247.6 linkuse as main transcript	c.64C>T	p.Arg22Cys	missense_variant	2/6	2			Q66GS9-2
CEP135	ENST00000506809.1 linkuse as main transcript	n.224C>T		non_coding_transcript_exon_variant	2/2	3
CEP135	ENST00000706800.1 linkuse as main transcript	n.237C>T		non_coding_transcript_exon_variant	2/5

Frequencies

GnomAD3 genomes

AF:

0.00101

AC:

153

AN:

152078

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00336

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000524

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00144

GnomAD3 exomes

AF:

0.000255

AC:

AN:

251344

Hom.:

AF XY:

0.000184

AC XY:

AN XY:

135864

show subpopulations

Gnomad AFR exome

AF:

0.00295

Gnomad AMR exome

AF:

0.0000868

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.000106

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000116

AC:

169

AN:

1460954

Hom.:

Cov.:

AF XY:

0.0000922

AC XY:

AN XY:

726866

show subpopulations

Gnomad4 AFR exome

AF:

0.00308

Gnomad4 AMR exome

AF:

0.000112

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.0000405

Gnomad4 OTH exome

AF:

0.000215

GnomAD4 genome

AF:

0.00101

AC:

153

AN:

152196

Hom.:

Cov.:

AF XY:

0.000994

AC XY:

AN XY:

74410

show subpopulations

Gnomad4 AFR

AF:

0.00335

Gnomad4 AMR

AF:

0.000523

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.000237

Hom.:

Bravo

AF:

0.00111

ESP6500AA

AF:

0.00318

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000305

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 12, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Nov 06, 2019	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jan 19, 2018

- -

CEP135-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 03, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.27

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.14

.;T

Eigen

Uncertain

0.31

Eigen_PC

Uncertain

0.30

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.96

D;D

M_CAP

Benign

0.069

MetaRNN

Benign

0.018

T;T

MetaSVM

Benign

-0.84

MutationAssessor

Uncertain

2.6

M;M

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.70

PROVEAN

Pathogenic

-6.0

D;D

REVEL

Benign

0.27

Sift

Uncertain

0.0010

D;D

Sift4G

Pathogenic

0.0010

D;D

Polyphen

1.0

D;D

Vest4

0.62

MVP

0.64

MPC

0.41

ClinPred

0.26

GERP RS

4.2

Varity_R

0.27

gMVP

0.46

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

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