21-45492744-G-GCCCGCCACTGCACT

Variant names:

• chr21-45492744-G-GCCCGCCACTGCACT
• rs11267376
• NM_001379500.1:c.2214+35_2214+36insCCACTGCACTCCCG

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_001379500.1(COL18A1):​c.2214+35_2214+36insCCACTGCACTCCCG variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000715 in 1,399,390 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 0)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: COL18A1 NM_001379500.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.588
• 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 1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, G2P
• Knobloch syndrome

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Laboratory for Molecular Medicine, Orphanet
• hereditary glaucoma, primary closed-angle

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001379500.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL18A1	NM_001379500.1	MANE Select	c.2214+35_2214+36insCCACTGCACTCCCG		intron	N/A	NP_001366429.1
	COL18A1	NM_130444.3		c.3459+35_3459+36insCCACTGCACTCCCG		intron	N/A	NP_569711.2
	COL18A1	NM_030582.4		c.2754+35_2754+36insCCACTGCACTCCCG		intron	N/A	NP_085059.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL18A1	ENST00000651438.1	MANE Select	c.2214+31_2214+32insCCCGCCACTGCACT		intron	N/A	ENSP00000498485.1
	COL18A1	ENST00000355480.10	TSL:1	c.2754+31_2754+32insCCCGCCACTGCACT		intron	N/A	ENSP00000347665.5
	COL18A1	ENST00000359759.8	TSL:5	c.3459+31_3459+32insCCCGCCACTGCACT		intron	N/A	ENSP00000352798.4

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD4 exome AF: 7.15e-7 AC: 1 AN: 1399390 Hom.: 0 Cov.: 28 AF XY: 0.00000143 AC XY: 1 AN XY: 699236

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 32026

American (AMR) AF: 0.00 AC: 0 AN: 44614

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25686

East Asian (EAS) AF: 0.00 AC: 0 AN: 39436

South Asian (SAS) AF: 0.00 AC: 0 AN: 85062

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 44826

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4354

European-Non Finnish (NFE) AF: 9.39e-7 AC: 1 AN: 1065046

Other (OTH) AF: 0.00 AC: 0 AN: 58340

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.59

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs11267376; hg19: chr21-46912658;