rs12482088

chr21-45482059-A-C

Variant summary

Our verdict is Benign. Variant got -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:4
• Conservation: PhyloP100: 0.0730

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]

ACMG classification

Verdict is Benign. Variant got -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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL18A1	NM_001379500.1	c.1674+34A>C		intron_variant		ENST00000651438.1
COL18A1	NM_030582.4	c.2214+34A>C		intron_variant
COL18A1	NM_130444.3	c.2919+34A>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL18A1	ENST00000651438.1	c.1674+34A>C		intron_variant			NM_001379500.1
COL18A1	ENST00000355480.10	c.2214+34A>C		intron_variant		1
COL18A1	ENST00000359759.8	c.2919+34A>C		intron_variant		5		P1

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

GnomAD3 exomes AF: 0.220 AC: 51289 AN: 233228 Hom.: 5548 AF XY: 0.219 AC XY: 27731 AN XY: 126804

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 SAS exome AF: 0.180

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

Gnomad4 AFR exome AF: 0.233

Gnomad4 AMR exome AF: 0.229

Gnomad4 ASJ exome AF: 0.270

Gnomad4 EAS exome AF: 0.123

Gnomad4 SAS exome AF: 0.183

Gnomad4 FIN exome AF: 0.208

Gnomad4 NFE exome AF: 0.243

Gnomad4 OTH exome AF: 0.226

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

Gnomad4 AFR AF: 0.231

Gnomad4 AMR AF: 0.239

Gnomad4 ASJ AF: 0.261

Gnomad4 EAS AF: 0.140

Gnomad4 SAS AF: 0.186

Gnomad4 FIN AF: 0.213

Gnomad4 NFE AF: 0.237

Gnomad4 OTH AF: 0.242

Alfa AF: 0.236 Hom.: 755

Bravo AF: 0.232

Asia WGS AF: 0.179 AC: 623 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Glaucoma, primary closed-angle Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 22, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 10, 2021

- -

Knobloch syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 22, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
Cadd	Benign	6.2
Dann	Benign	0.26

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

Publications

LitVar

Other links and lift over

dbSNP: rs12482088; hg19: chr21-46901973;