21-45429366-T-C

Variant names:

• chr21-45429366-T-C
• rs2026887
• NM_001379500.1:c.106+23893T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001379500.1(COL18A1):​c.106+23893T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.411 in 152,094 control chromosomes in the GnomAD database, including 15,023 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.41 (15023 hom., cov: 32)
• Consequence: COL18A1 NM_001379500.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -5.23
• 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.06).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.669 is higher than 0.05.

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.106+23893T>C		intron	N/A	NP_001366429.1	P39060-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL18A1	ENST00000651438.1	MANE Select	c.106+23893T>C		intron	N/A	ENSP00000498485.1	P39060-2
	COL18A1	ENST00000859062.1		c.106+23893T>C		intron	N/A	ENSP00000529121.1
	COL18A1	ENST00000930602.1		c.106+23893T>C		intron	N/A	ENSP00000600661.1

Frequencies

GnomAD3 genomes AF: 0.411 AC: 62387 AN: 151976 Hom.: 14983 Cov.: 32

Gnomad AFR AF: 0.675

Gnomad AMI AF: 0.424

Gnomad AMR AF: 0.382

Gnomad ASJ AF: 0.318

Gnomad EAS AF: 0.514

Gnomad SAS AF: 0.292

Gnomad FIN AF: 0.343

Gnomad MID AF: 0.370

Gnomad NFE AF: 0.273

Gnomad OTH AF: 0.368

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.411 AC: 62492 AN: 152094 Hom.: 15023 Cov.: 32 AF XY: 0.412 AC XY: 30638 AN XY: 74346

African (AFR) AF: 0.675 AC: 28015 AN: 41494

American (AMR) AF: 0.382 AC: 5848 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.318 AC: 1104 AN: 3468

East Asian (EAS) AF: 0.514 AC: 2654 AN: 5162

South Asian (SAS) AF: 0.293 AC: 1414 AN: 4822

European-Finnish (FIN) AF: 0.343 AC: 3628 AN: 10570

Middle Eastern (MID) AF: 0.361 AC: 106 AN: 294

European-Non Finnish (NFE) AF: 0.273 AC: 18564 AN: 67976

Other (OTH) AF: 0.367 AC: 773 AN: 2108

Alfa AF: 0.348 Hom.: 1310

Bravo AF: 0.426

Asia WGS AF: 0.422 AC: 1467 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.1
CADD	Benign	0.57
DANN	Benign	0.11
PhyloP100		-5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs2026887; hg19: chr21-46849281;