10-93503185-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_018131.5(CEP55):c.256C>T(p.Arg86*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000449 in 1,613,690 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.00017 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00048 ( 0 hom. )

Consequence

CEP55
NM_018131.5 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: 0.00600

Variant links:

Genes affected

CEP55 (HGNC:1161): (centrosomal protein 55) Enables identical protein binding activity. Involved in cranial skeletal system development; establishment of protein localization; and midbody abscission. Acts upstream of or within mitotic cytokinesis. Located in Flemming body; centriolar satellite; and plasma membrane. Implicated in multinucleated neurons, anhydramnios, renal dysplasia, cerebellar hypoplasia and hydranencephaly. [provided by Alliance of Genome Resources, Apr 2022]

CEP55 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 10-93503185-C-T is Pathogenic according to our data. Variant chr10-93503185-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 437875.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CEP55	NM_018131.5 link	c.256C>T	p.Arg86*	stop_gained	Exon 3 of 9	ENST00000371485.8	NP_060601.4	Q53EZ4-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CEP55	ENST00000371485.8 link	c.256C>T	p.Arg86*	stop_gained	Exon 3 of 9	1	NM_018131.5	ENSP00000360540.3		Q53EZ4-1

Frequencies

GnomAD3 genomes

AF:

0.000171

AC:

AN:

152062

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000725

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000944

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000279

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000282

AC:

AN:

251356

Hom.:

AF XY:

0.000228

AC XY:

AN XY:

135830

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000139

Gnomad NFE exome

AF:

0.000378

Gnomad OTH exome

AF:

0.000489

GnomAD4 exome

AF:

0.000478

AC:

698

AN:

1461628

Hom.:

Cov.:

AF XY:

0.000446

AC XY:

324

AN XY:

727140

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

Gnomad4 AMR exome

AF:

0.000470

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.000262

Gnomad4 NFE exome

AF:

0.000576

Gnomad4 OTH exome

AF:

0.000298

GnomAD4 genome

AF:

0.000171

AC:

AN:

152062

Hom.:

Cov.:

AF XY:

0.000202

AC XY:

AN XY:

74252

show subpopulations

Gnomad4 AFR

AF:

0.0000725

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000944

Gnomad4 NFE

AF:

0.000279

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.000355

Hom.:

Bravo

AF:

0.000227

TwinsUK

AF:

0.00135

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000379

AC:

EpiCase

AF:

0.000763

EpiControl

AF:

0.000296

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Multinucleated neurons-anhydramnios-renal dysplasia-cerebellar hypoplasia-hydranencephaly syndrome

Pathogenic:4

Aug 31, 2021

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 22, 2020

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in compound heterozygosity with variant NM_018131.5:c.256C>T -

Aug 28, 2017

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This nonsense variant found in exon 3 of 9 and is predicted to result in loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay (NMD). This variant has been previously reported as a homozygous change in a fetus with a prenatal lethal phenotype consistent with Multinucleated neurons, Anhydramnios, Renal dysplasia, Cerebellar hypoplasia, and Hydranencephaly (MARCH) syndrome, and as a compound heterozygous change in an infant with microcephaly, speech delay, and bilateral toe syndactyly (MIM: #236500; PMID: 28295209, 32100459). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.03% (80/282750) and thus is presumed to be rare. Based on the available evidence, the c.256C>T (p.Arg86Ter) variant is classified as Pathogenic. -

not provided

Pathogenic:2

Sep 01, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Published functional studies suggest a damaging effect on cilia disassembly (Zhang et al., 2019); This variant is associated with the following publications: (PMID: 30622327, 32100459, 28295209, 33475699) -

Sep 17, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Arg86*) in the CEP55 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CEP55 are known to be pathogenic (PMID: 28264986, 28295209, 30622327). This variant is present in population databases (rs141458677, gnomAD 0.06%). This premature translational stop signal has been observed in individual(s) with clinical features of Meckel-Gruber syndrome (PMID: 28295209, 32100459). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 437875). For these reasons, this variant has been classified as Pathogenic. -

Inborn genetic diseases

Pathogenic:1

Dec 04, 2020

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.256C>T (p.R86*) alteration, located in exon 3 (coding exon 2) of the CEP55 gene, consists of a C to T substitution at nucleotide position 256. This changes the amino acid from an arginine (R) to a stop codon at amino acid position 86. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This mutation was identified in the homozygous state in a fetus with Meckel-like syndrome; both parents and an unaffected sibling were heterozygous (Bondeson, 2017). This mutation was also detected in trans with a missense variant in two individuals with developmental delay, microcephaly/borderline microcephaly, and dysmorphic features (Barrie, 2020). Based on the available evidence, this alteration is classified as pathogenic. -

CEP55-related disorder

Pathogenic:1

Sep 05, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The CEP55 c.256C>T variant is predicted to result in premature protein termination (p.Arg86*). This variant in the homozygous condition or along with a second variant in CEP55 was reported in two individuals with Meckel-like syndrome (Bondeson et al. 2017. PubMed ID: 28295209; Barrie et al. 2020. PubMed ID: 32100459). Functional studies suggest that this variant led to disrupted dynamic regulation of cilia formation (Zhang et al. 2021. PubMed ID: 33475699). This variant is reported in 0.056% of alleles in individuals of Latino descent in gnomAD. Nonsense variants in CEP55 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Uncertain

0.15

BayesDel_noAF

Pathogenic

0.40

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Uncertain

0.45

Eigen_PC

Uncertain

0.26

FATHMM_MKL

Benign

0.38

Vest4

0.83

GERP RS

2.4

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