rs12482088

Variant names:

• chr21-45482059-A-C
• rs12482088
• NM_001379500.1:c.1674+34A>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001379500.1(COL18A1):​c.1674+34A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.233 in 1,565,148 control chromosomes in the GnomAD database, including 42,774 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.23 (3961 hom., cov: 34)
  • Exomes 𝑓: 0.23 (38813 hom.)
• Consequence: COL18A1 NM_001379500.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.0730
• Publications: 16 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).
• BP6: Variant 21-45482059-A-C is Benign according to our data. Variant chr21-45482059-A-C is described in ClinVar as Benign. ClinVar VariationId is 261892.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.234 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.1674+34A>C		intron	N/A	NP_001366429.1	P39060-2
	COL18A1	NM_130444.3		c.2919+34A>C		intron	N/A	NP_569711.2
	COL18A1	NM_030582.4		c.2214+34A>C		intron	N/A	NP_085059.2	A0AAG2UXZ5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL18A1	ENST00000651438.1	MANE Select	c.1674+34A>C		intron	N/A	ENSP00000498485.1	P39060-2
	COL18A1	ENST00000355480.10	TSL:1	c.2214+34A>C		intron	N/A	ENSP00000347665.5	P39060-1
	COL18A1	ENST00000359759.8	TSL:5	c.2919+34A>C		intron	N/A	ENSP00000352798.4	P39060-3

Frequencies

GnomAD3 genomes AF: 0.229 AC: 34803 AN: 152110 Hom.: 3958 Cov.: 34

Gnomad AFR AF: 0.231

Gnomad AMI AF: 0.0987

Gnomad AMR AF: 0.239

Gnomad ASJ AF: 0.261

Gnomad EAS AF: 0.140

Gnomad SAS AF: 0.185

Gnomad FIN AF: 0.213

Gnomad MID AF: 0.256

Gnomad NFE AF: 0.237

Gnomad OTH AF: 0.244

GnomAD2 exomes AF: 0.220 AC: 51289 AN: 233228 AF XY: 0.219

Gnomad AFR exome AF: 0.232

Gnomad AMR exome AF: 0.224

Gnomad ASJ exome AF: 0.262

Gnomad EAS exome AF: 0.140

Gnomad FIN exome AF: 0.215

Gnomad NFE exome AF: 0.238

Gnomad OTH exome AF: 0.227

GnomAD4 exome AF: 0.234 AC: 330593 AN: 1412920 Hom.: 38813 Cov.: 25 AF XY: 0.232 AC XY: 163775 AN XY: 704918

African (AFR) AF: 0.233 AC: 7595 AN: 32540

American (AMR) AF: 0.229 AC: 10043 AN: 43904

Ashkenazi Jewish (ASJ) AF: 0.270 AC: 6951 AN: 25734

East Asian (EAS) AF: 0.123 AC: 4819 AN: 39304

South Asian (SAS) AF: 0.183 AC: 15449 AN: 84566

European-Finnish (FIN) AF: 0.208 AC: 10956 AN: 52776

Middle Eastern (MID) AF: 0.256 AC: 1452 AN: 5668

European-Non Finnish (NFE) AF: 0.243 AC: 260078 AN: 1069820

Other (OTH) AF: 0.226 AC: 13250 AN: 58608

GnomAD4 genome AF: 0.229 AC: 34823 AN: 152228 Hom.: 3961 Cov.: 34 AF XY: 0.227 AC XY: 16923 AN XY: 74426

African (AFR) AF: 0.231 AC: 9603 AN: 41550

American (AMR) AF: 0.239 AC: 3656 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.261 AC: 904 AN: 3470

East Asian (EAS) AF: 0.140 AC: 724 AN: 5168

South Asian (SAS) AF: 0.186 AC: 895 AN: 4824

European-Finnish (FIN) AF: 0.213 AC: 2261 AN: 10612

Middle Eastern (MID) AF: 0.265 AC: 78 AN: 294

European-Non Finnish (NFE) AF: 0.237 AC: 16101 AN: 67980

Other (OTH) AF: 0.242 AC: 511 AN: 2112

Alfa AF: 0.235 Hom.: 1253

Bravo AF: 0.232

Asia WGS AF: 0.179 AC: 623 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Hereditary glaucoma, primary closed-angle (1)
-	-	1	Knobloch syndrome (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	6.2
DANN	Benign	0.26
PhyloP100		0.073
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: rs12482088; hg19: chr21-46901973; COSMIC: COSV107443048; COSMIC: COSV107443048;