4-56011797-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_025009.5(CEP135):c.2617-3C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000326 in 1,564,748 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000021 ( 0 hom. )

Consequence

CEP135
NM_025009.5 splice_region, intron

Scores

Splicing: ADA: 0.0005210

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 0.631

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.35).

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
CEP135	NM_025009.5 link	c.2617-3C>T	splice_region_variant, intron_variant	Intron 20 of 25	ENST00000257287.5	NP_079285.2	Q66GS9-1
CEP135	XM_006714055.4 link	c.2584-3C>T	splice_region_variant, intron_variant	Intron 20 of 25		XP_006714118.1
CEP135	XM_005265788.5 link	c.1546-3C>T	splice_region_variant, intron_variant	Intron 13 of 18		XP_005265845.1
CEP135	XM_011534412.2 link	c.1087-3C>T	splice_region_variant, intron_variant	Intron 10 of 15		XP_011532714.1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
CEP135	ENST00000257287.5 link	c.2617-3C>T	splice_region_variant, intron_variant	Intron 20 of 25	1	NM_025009.5	ENSP00000257287.3	Q66GS9-1
CEP135	ENST00000506202.1 link	n.2567-3C>T	splice_region_variant, intron_variant	Intron 13 of 18	1
CEP135	ENST00000706801.1 link	n.682-3C>T	splice_region_variant, intron_variant	Intron 4 of 9

Frequencies

GnomAD3 genomes

AF:

0.000138

AC:

AN:

151776

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000460

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.000208

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000529

AC:

AN:

207864

AF XY:

0.00000882

show subpopulations

Gnomad AFR exome

AF:

0.000480

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000193

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000212

AC:

AN:

1412854

Hom.:

Cov.:

AF XY:

0.0000171

AC XY:

AN XY:

701596

show subpopulations

African (AFR)

AF:

0.000231

AC:

AN:

30336

American (AMR)

AF:

0.00

AC:

AN:

31440

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23660

East Asian (EAS)

AF:

0.000130

AC:

AN:

38426

South Asian (SAS)

AF:

0.0000510

AC:

AN:

78404

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52580

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5522

European-Non Finnish (NFE)

AF:

0.00000183

AC:

AN:

1094384

Other (OTH)

AF:

0.000207

AC:

AN:

58102

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000138

AC:

AN:

151894

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74240

show subpopulations

African (AFR)

AF:

0.000459

AC:

AN:

41404

American (AMR)

AF:

0.00

AC:

AN:

15254

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.000194

AC:

AN:

5156

South Asian (SAS)

AF:

0.000208

AC:

AN:

4812

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10522

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67960

Other (OTH)

AF:

0.00

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.554

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000164

Hom.:

Bravo

AF:

0.000147

Asia WGS

AF:

0.00144

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 27, 2016

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Uncertain:1

Oct 15, 2021

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.2617-3C>T intronic alteration consists of a C to T substitution 3 nucleotides before exon 21 (coding exon 20) of the CEP135 gene. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Uncertain:1

Sep 27, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. ClinVar contains an entry for this variant (Variation ID: 434725). This variant has not been reported in the literature in individuals affected with CEP135-related conditions. This variant is present in population databases (rs377744366, gnomAD 0.05%). This sequence change falls in intron 20 of the CEP135 gene. It does not directly change the encoded amino acid sequence of the CEP135 protein. It affects a nucleotide within the consensus splice site. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.35

CADD

Benign

9.6

(source)

DANN

Benign

0.62

PhyloP100

0.63

Mutation Taster

=98/2

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00052

dbscSNV1_RF

Benign

0.17

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

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4-56011797-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over