10-93528032-C-A
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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
NM_018131.5 stop_gained
Scores
3
3
1
Clinical Significance
Conservation
PhyloP100: 3.27
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]
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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 |
---|---|---|---|---|---|---|---|
CEP55 | NM_018131.5 | c.1274C>A | p.Ser425Ter | stop_gained | 9/9 | ENST00000371485.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CEP55 | ENST00000371485.8 | c.1274C>A | p.Ser425Ter | stop_gained | 9/9 | 1 | NM_018131.5 | P1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
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GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251382Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135862
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GnomAD4 exome AF: 0.00000752 AC: 11AN: 1461838Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5AN XY: 727222
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GnomAD4 genome Cov.: 32
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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 provided | literature only | OMIM | Aug 28, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital | Jul 30, 2018 | PVS1, 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 submitter | clinical testing | Revvity Omics, Revvity | Aug 31, 2021 | - - |
Computational scores
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Name
Calibrated prediction
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Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
MutationTaster
Benign
D
Vest4
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at