rs11702782

Variant names:

• chr21-45428674-G-A
• rs11702782
• NM_001379500.1:c.106+23201G>A

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+23201G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.126 in 152,038 control chromosomes in the GnomAD database, including 1,447 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 0.13 (1447 hom., cov: 32)
• Consequence: COL18A1 NM_001379500.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.147
• Publications: 10 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.165 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL18A1	NM_001379500.1	c.106+23201G>A		intron_variant	Intron 2 of 41	ENST00000651438.1	NP_001366429.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL18A1	ENST00000651438.1	c.106+23201G>A		intron_variant	Intron 2 of 41		NM_001379500.1	ENSP00000498485.1

Frequencies

GnomAD3 genomes AF: 0.126 AC: 19123 AN: 151920 Hom.: 1449 Cov.: 32

Gnomad AFR AF: 0.0322

Gnomad AMI AF: 0.0921

Gnomad AMR AF: 0.171

Gnomad ASJ AF: 0.167

Gnomad EAS AF: 0.105

Gnomad SAS AF: 0.112

Gnomad FIN AF: 0.158

Gnomad MID AF: 0.139

Gnomad NFE AF: 0.168

Gnomad OTH AF: 0.145

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

GnomAD4 genome AF: 0.126 AC: 19112 AN: 152038 Hom.: 1447 Cov.: 32 AF XY: 0.127 AC XY: 9402 AN XY: 74298

African (AFR) AF: 0.0321 AC: 1330 AN: 41488

American (AMR) AF: 0.171 AC: 2607 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.167 AC: 577 AN: 3464

East Asian (EAS) AF: 0.104 AC: 538 AN: 5164

South Asian (SAS) AF: 0.112 AC: 538 AN: 4816

European-Finnish (FIN) AF: 0.158 AC: 1669 AN: 10552

Middle Eastern (MID) AF: 0.136 AC: 40 AN: 294

European-Non Finnish (NFE) AF: 0.168 AC: 11423 AN: 67976

Other (OTH) AF: 0.145 AC: 306 AN: 2114

Alfa AF: 0.160 Hom.: 3299

Bravo AF: 0.125

Asia WGS AF: 0.122 AC: 423 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	2.5
DANN	Benign	0.61
PhyloP100		-0.15
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: rs11702782; hg19: chr21-46848589;