chr3-9940950-CG-C
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1PM2
The NM_001077415.3(CRELD1):c.566del(p.Gly189ValfsTer56) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000274 in 1,461,870 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 31)
Exomes 𝑓: 0.0000027 ( 0 hom. )
Consequence
CRELD1
NM_001077415.3 frameshift
NM_001077415.3 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 3.94
Genes affected
CRELD1 (HGNC:14630): (cysteine rich with EGF like domains 1) This gene encodes a member of a subfamily of epidermal growth factor-related proteins. The encoded protein is characterized by a cysteine-rich with epidermal growth factor-like domain. This protein may function as a cell adhesion molecule. Mutations in this gene are the cause of atrioventricular septal defect. Alternate splicing results in multiple transcript variants.[provided by RefSeq, Apr 2010]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 10 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;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CRELD1 | NM_001077415.3 | c.566del | p.Gly189ValfsTer56 | frameshift_variant | 6/11 | ENST00000452070.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CRELD1 | ENST00000452070.6 | c.566del | p.Gly189ValfsTer56 | frameshift_variant | 6/11 | 2 | NM_001077415.3 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 31
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31
GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251238Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135856
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GnomAD4 exome AF: 0.00000274 AC: 4AN: 1461870Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1AN XY: 727234
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GnomAD4 genome ? Cov.: 31
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Atrioventricular septal defect, susceptibility to, 2 Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Dec 16, 2020 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Nov 06, 2021 | Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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. This variant has not been reported in the literature in individuals affected with CRELD1-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.006%). This sequence change creates a premature translational stop signal (p.Gly189Valfs*56) in the CRELD1 gene. It is expected to result in an absent or disrupted protein product. However, the current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in CRELD1 cause disease. - |
Computational scores
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at