chr21-45483498-C-T

Variant names:

• chr21-45483498-C-T
• rs2236472
• NM_001379500.1:c.1701+677C>T

Variant summary

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

The NM_001379500.1(COL18A1):​c.1701+677C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.194 in 151,972 control chromosomes in the GnomAD database, including 3,000 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 0.19 (3000 hom., cov: 33)
• Consequence: COL18A1 NM_001379500.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.279
• Publications: 26 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=-0.96).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.231 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.1701+677C>T		intron	N/A	NP_001366429.1
	COL18A1	NM_130444.3		c.2946+677C>T		intron	N/A	NP_569711.2
	COL18A1	NM_030582.4		c.2241+677C>T		intron	N/A	NP_085059.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL18A1	ENST00000651438.1	MANE Select	c.1701+677C>T		intron	N/A	ENSP00000498485.1
	COL18A1	ENST00000355480.10	TSL:1	c.2241+677C>T		intron	N/A	ENSP00000347665.5
	COL18A1	ENST00000359759.8	TSL:5	c.2946+677C>T		intron	N/A	ENSP00000352798.4

Frequencies

GnomAD3 genomes AF: 0.194 AC: 29419 AN: 151852 Hom.: 3000 Cov.: 33

Gnomad AFR AF: 0.116

Gnomad AMI AF: 0.0965

Gnomad AMR AF: 0.225

Gnomad ASJ AF: 0.256

Gnomad EAS AF: 0.140

Gnomad SAS AF: 0.183

Gnomad FIN AF: 0.207

Gnomad MID AF: 0.250

Gnomad NFE AF: 0.234

Gnomad OTH AF: 0.216

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

GnomAD4 genome AF: 0.194 AC: 29422 AN: 151972 Hom.: 3000 Cov.: 33 AF XY: 0.194 AC XY: 14399 AN XY: 74264

African (AFR) AF: 0.116 AC: 4801 AN: 41468

American (AMR) AF: 0.225 AC: 3430 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.256 AC: 890 AN: 3470

East Asian (EAS) AF: 0.141 AC: 723 AN: 5136

South Asian (SAS) AF: 0.183 AC: 879 AN: 4812

European-Finnish (FIN) AF: 0.207 AC: 2189 AN: 10560

Middle Eastern (MID) AF: 0.259 AC: 75 AN: 290

European-Non Finnish (NFE) AF: 0.234 AC: 15895 AN: 67940

Other (OTH) AF: 0.214 AC: 452 AN: 2112

Alfa AF: 0.226 Hom.: 6263

Bravo AF: 0.192

Asia WGS AF: 0.171 AC: 596 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	5.3
DANN	Benign	0.48
PhyloP100		-0.28
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs2236472; hg19: chr21-46903412; COSMIC: COSV62699813;