10-93528032-C-A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_ModeratePM2PP5_Very_Strong

The NM_018131.5(CEP55):​c.1274C>A​(p.Ser425Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000752 in 1,461,838 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000075 ( 0 hom. )

Consequence

CEP55
NM_018131.5 stop_gained

Scores

3
3
1

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 3.27
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0867 CDS is truncated, and there are 1 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 10-93528032-C-A is Pathogenic according to our data. Variant chr10-93528032-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 437874.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
CEP55NM_018131.5 linkuse as main transcriptc.1274C>A p.Ser425Ter stop_gained 9/9 ENST00000371485.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
CEP55ENST00000371485.8 linkuse as main transcriptc.1274C>A p.Ser425Ter stop_gained 9/91 NM_018131.5 P1Q53EZ4-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.0000119
AC:
3
AN:
251382
Hom.:
0
AF XY:
0.00000736
AC XY:
1
AN XY:
135862
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:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000264
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000752
AC:
11
AN:
1461838
Hom.:
0
Cov.:
31
AF XY:
0.00000688
AC XY:
5
AN XY:
727222
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:
0.00
Gnomad4 FIN exome
AF:
0.0000374
Gnomad4 NFE exome
AF:
0.00000809
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
Alfa
AF:
0.0000401
Hom.:
0
Bravo
AF:
0.0000151
ExAC
AF:
0.0000165
AC:
2
EpiCase
AF:
0.00
EpiControl
AF:
0.0000593

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Multinucleated neurons-anhydramnios-renal dysplasia-cerebellar hypoplasia-hydranencephaly syndrome Pathogenic:3
Pathogenic, no assertion criteria providedliterature onlyOMIMAug 28, 2017- -
Pathogenic, criteria provided, single submitterclinical testingInstitute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's HospitalJul 30, 2018PVS1, PS3, PM2, PP1; This paternally-inherited nonsense variant [c.1274C>A, (p.Ser425Ter)] is predicted to be a truncating alteration in a gene where loss-of-function is a known mechanism of disease (ACMG: PVS1). In vitro studies of this variant demonstrated decreased mRNA expression and mislocalization of the protein (PMID: 28264986) (ACMG: PS3). The variant is rare in large-scale population databases (ACMG: PM2), yet homozygosity for this variant has been observed to cosegregate with disease (MARCH syndrome) in a family with multiple affected children (PMID: 28264986)(ACMG: PP1). No evidence was found to support any of the Benign ACMG criteria, therefore this alteration meets ACMG guidelines for classification as a Pathogenic variant. Of note, a maternally-inherited missense variant of uncertain significance [c.70G>A, (p.Glu24Lys)] in CEP55 was also detected in this individual. This second alteration, presumably in trans (ACMG: PM3), was also rare in large-scale population databases (ACMG: PM2); however, insufficient evidence was available to warrant pathogenic or likely pathogenic classification using ACMG criteria. -
Pathogenic, criteria provided, single submitterclinical testingRevvity Omics, RevvityAug 31, 2021- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.58
D
BayesDel_noAF
Pathogenic
0.65
CADD
Pathogenic
34
DANN
Uncertain
1.0
Eigen
Pathogenic
0.73
Eigen_PC
Uncertain
0.60
FATHMM_MKL
Uncertain
0.97
D
MutationTaster
Benign
1.0
D
Vest4
0.84
GERP RS
6.0

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.

Other links and lift over

dbSNP: rs201430235; hg19: chr10-95287789; API