NM_001379500.1:c.1800_1808dupTGGGCCCCC

Variant names:

• chr21-45486944-C-CCCCCCTGGG
• rs764710670
• NM_001379500.1:c.1800_1808dupTGGGCCCCC

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM4

The NM_001379500.1(COL18A1):​c.1800_1808dupTGGGCCCCC​(p.Pro603_Gly604insGlyProPro) variant causes a disruptive inframe insertion change. The variant allele was found at a frequency of 0.0000451 in 1,486,468 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. P603P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000049 (0 hom.)
• Consequence: COL18A1 NM_001379500.1 disruptive_inframe_insertion
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.80
• Publications: 2 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: ClinGen, G2P, Labcorp Genetics (formerly Invitae)
• 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 2 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_001379500.1.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL18A1	NM_001379500.1	MANE Select	c.1800_1808dupTGGGCCCCC	p.Pro603_Gly604insGlyProPro	disruptive_inframe_insertion	Exon 16 of 42	NP_001366429.1	P39060-2
	COL18A1	NM_130444.3		c.3045_3053dupTGGGCCCCC	p.Pro1018_Gly1019insGlyProPro	disruptive_inframe_insertion	Exon 15 of 41	NP_569711.2
	COL18A1	NM_030582.4		c.2340_2348dupTGGGCCCCC	p.Pro783_Gly784insGlyProPro	disruptive_inframe_insertion	Exon 15 of 41	NP_085059.2	A0AAG2UXZ5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL18A1	ENST00000651438.1	MANE Select	c.1800_1808dupTGGGCCCCC	p.Pro603_Gly604insGlyProPro	disruptive_inframe_insertion	Exon 16 of 42	ENSP00000498485.1	P39060-2
	COL18A1	ENST00000355480.10	TSL:1	c.2340_2348dupTGGGCCCCC	p.Pro783_Gly784insGlyProPro	disruptive_inframe_insertion	Exon 15 of 41	ENSP00000347665.5	P39060-1
	COL18A1	ENST00000359759.8	TSL:5	c.3045_3053dupTGGGCCCCC	p.Pro1018_Gly1019insGlyProPro	disruptive_inframe_insertion	Exon 15 of 41	ENSP00000352798.4	P39060-3

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151956 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.0000654 AC: 7 AN: 107000 AF XY: 0.0000342

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000942

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000487 AC: 65 AN: 1334512 Hom.: 0 Cov.: 30 AF XY: 0.0000488 AC XY: 32 AN XY: 656314

African (AFR) AF: 0.00 AC: 0 AN: 28982

American (AMR) AF: 0.0000732 AC: 2 AN: 27314

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21576

East Asian (EAS) AF: 0.00 AC: 0 AN: 34614

South Asian (SAS) AF: 0.0000832 AC: 6 AN: 72124

European-Finnish (FIN) AF: 0.0000238 AC: 1 AN: 42034

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3780

European-Non Finnish (NFE) AF: 0.0000419 AC: 44 AN: 1048922

Other (OTH) AF: 0.000218 AC: 12 AN: 55166

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 151956 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74224

African (AFR) AF: 0.00 AC: 0 AN: 41378

American (AMR) AF: 0.00 AC: 0 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5130

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67954

Other (OTH) AF: 0.000478 AC: 1 AN: 2090

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.8
Mutation Taster		=77/23	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs764710670; hg19: chr21-46906858;