10-93503185-C-T
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
Consequence
NM_018131.5 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000171 AC: 26AN: 152062Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000282 AC: 71AN: 251356Hom.: 0 AF XY: 0.000228 AC XY: 31AN XY: 135830
GnomAD4 exome AF: 0.000478 AC: 698AN: 1461628Hom.: 0 Cov.: 31 AF XY: 0.000446 AC XY: 324AN XY: 727140
GnomAD4 genome AF: 0.000171 AC: 26AN: 152062Hom.: 0 Cov.: 33 AF XY: 0.000202 AC XY: 15AN XY: 74252
ClinVar
Submissions by phenotype
Multinucleated neurons-anhydramnios-renal dysplasia-cerebellar hypoplasia-hydranencephaly syndrome Pathogenic:4
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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. -
This variant was observed in compound heterozygosity with variant NM_018131.5:c.256C>T -
not provided Pathogenic:2
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. -
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) -
Inborn genetic diseases Pathogenic:1
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
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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at