rs786201015
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 10P and 1B. PVS1PM2BS1_Supporting
The NM_001378328.1(CELSR1):c.5052_5053dupTG(p.Glu1685ValfsTer22) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000205 in 1,460,992 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as risk factor (no stars). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000021 ( 0 hom. )
Consequence
CELSR1
NM_001378328.1 frameshift
NM_001378328.1 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 5.73
Genes affected
CELSR1 (HGNC:1850): (cadherin EGF LAG seven-pass G-type receptor 1) The protein encoded by this gene is a member of the flamingo subfamily, part of the cadherin superfamily. The flamingo subfamily consists of nonclassic-type cadherins; a subpopulation that does not interact with catenins. The flamingo cadherins are located at the plasma membrane and have nine cadherin domains, seven epidermal growth factor-like repeats and two laminin A G-type repeats in their ectodomain. They also have seven transmembrane domains, a characteristic unique to this subfamily. It is postulated that these proteins are receptors involved in contact-mediated communication, with cadherin domains acting as homophilic binding regions and the EGF-like domains involved in cell adhesion and receptor-ligand interactions. This particular member is a developmentally regulated, neural-specific gene which plays an unspecified role in early embryogenesis. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 9 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;
BS1
Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.00000205 (3/1460992) while in subpopulation AMR AF= 0.0000671 (3/44722). AF 95% confidence interval is 0.0000178. There are 0 homozygotes in gnomad4_exome. There are 1 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CELSR1 | NM_001378328.1 | c.5052_5053dupTG | p.Glu1685ValfsTer22 | frameshift_variant | Exon 8 of 35 | ENST00000674500.2 | NP_001365257.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
CELSR1 | ENST00000674500.2 | c.5052_5053dupTG | p.Glu1685ValfsTer22 | frameshift_variant | Exon 8 of 35 | NM_001378328.1 | ENSP00000501367.2 | |||
CELSR1 | ENST00000262738.9 | c.5052_5053dupTG | p.Glu1685ValfsTer22 | frameshift_variant | Exon 8 of 35 | 1 | ENSP00000262738.3 | |||
CELSR1 | ENST00000674359.1 | c.63_64dupTG | p.Glu22fs | frameshift_variant | Exon 1 of 10 | ENSP00000501512.1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD3 exomes AF: 0.0000120 AC: 3AN: 250830Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135678
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GnomAD4 exome AF: 0.00000205 AC: 3AN: 1460992Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1AN XY: 726874
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GnomAD4 genome Cov.: 32
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ClinVar
Significance: risk factor
Submissions summary: Other:1
Revision: no assertion criteria provided
LINK: link
Submissions by phenotype
Neural tube defects, susceptibility to Other:1
Jan 01, 2014
OMIM
Significance: risk factor
Review Status: no assertion criteria provided
Collection Method: literature only
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Computational scores
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Name
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Prediction
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at