21-45477808-GC-GCC
Variant names:
Variant summary
Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1PM2PP5
The NM_001379500.1(COL18A1):c.1070dupC(p.Gly358ArgfsTer55) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000143 in 1,398,288 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (no stars). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000014 ( 0 hom. )
Consequence
COL18A1
NM_001379500.1 frameshift
NM_001379500.1 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: -1.71
Publications
0 publications found
Genes affected
COL18A1 (HGNC:2195): (collagen type XVIII alpha 1 chain) This gene encodes the alpha chain of type XVIII collagen. This collagen is one of the multiplexins, extracellular matrix proteins that contain multiple triple-helix domains (collagenous domains) interrupted by non-collagenous domains. A long isoform of the protein has an N-terminal domain that is homologous to the extracellular part of frizzled receptors. Proteolytic processing at several endogenous cleavage sites in the C-terminal domain results in production of endostatin, a potent antiangiogenic protein that is able to inhibit angiogenesis and tumor growth. Mutations in this gene are associated with Knobloch syndrome. The main features of this syndrome involve retinal abnormalities, so type XVIII collagen may play an important role in retinal structure and in neural tube closure. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2014]
COL18A1 Gene-Disease associations (from GenCC):
- Knobloch syndrome 1Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, G2P
- Knobloch syndromeInheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Laboratory for Molecular Medicine, Orphanet
- hereditary glaucoma, primary closed-angleInheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
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ACMG classification
Classification was made for transcript
Our verdict: Pathogenic. The variant received 11 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;
PP5
Variant 21-45477808-G-GC is Pathogenic according to our data. Variant chr21-45477808-G-GC is described in ClinVar as Pathogenic. ClinVar VariationId is 548656.Status of the report is no_assertion_criteria_provided, 0 stars.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| COL18A1 | NM_001379500.1 | c.1070dupC | p.Gly358ArgfsTer55 | frameshift_variant | Exon 8 of 42 | ENST00000651438.1 | NP_001366429.1 | |
| COL18A1 | NM_130444.3 | c.2315dupC | p.Gly773ArgfsTer55 | frameshift_variant | Exon 7 of 41 | NP_569711.2 | ||
| COL18A1 | NM_030582.4 | c.1610dupC | p.Gly538ArgfsTer55 | frameshift_variant | Exon 7 of 41 | NP_085059.2 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| COL18A1 | ENST00000651438.1 | c.1070dupC | p.Gly358ArgfsTer55 | frameshift_variant | Exon 8 of 42 | NM_001379500.1 | ENSP00000498485.1 | |||
| COL18A1 | ENST00000355480.10 | c.1610dupC | p.Gly538ArgfsTer55 | frameshift_variant | Exon 7 of 41 | 1 | ENSP00000347665.5 | |||
| COL18A1 | ENST00000359759.8 | c.2315dupC | p.Gly773ArgfsTer55 | frameshift_variant | Exon 7 of 41 | 5 | ENSP00000352798.4 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
33
GnomAD4 exome AF: 0.00000143 AC: 2AN: 1398288Hom.: 0 Cov.: 33 AF XY: 0.00000145 AC XY: 1AN XY: 689752 show subpopulations
GnomAD4 exome
AF:
AC:
2
AN:
1398288
Hom.:
Cov.:
33
AF XY:
AC XY:
1
AN XY:
689752
show subpopulations
African (AFR)
AF:
AC:
0
AN:
31708
American (AMR)
AF:
AC:
0
AN:
35770
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
25130
East Asian (EAS)
AF:
AC:
0
AN:
35922
South Asian (SAS)
AF:
AC:
0
AN:
79278
European-Finnish (FIN)
AF:
AC:
1
AN:
47760
Middle Eastern (MID)
AF:
AC:
1
AN:
5676
European-Non Finnish (NFE)
AF:
AC:
0
AN:
1079058
Other (OTH)
AF:
AC:
0
AN:
57986
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.450
Heterozygous variant carriers
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0.95
Allele balance
Age Distribution
Exome Het
Variant carriers
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Age
GnomAD4 genome
GnomAD4 genome
Cov.:
33
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: no assertion criteria provided
LINK: link
Submissions by phenotype
Knobloch syndrome Pathogenic:1
Sep 04, 2014
Yale Center for Mendelian Genomics, Yale University
Significance:Pathogenic
Review Status:no assertion criteria provided
Collection Method:literature only
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
PhyloP100
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
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