rs2236456

Variant names:

• chr21-45473853-A-G
• rs2236456
• NM_001379500.1:c.652-42A>G

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.652-42A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.151 in 1,524,998 control chromosomes in the GnomAD database, including 22,125 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.23 (5834 hom., cov: 32)
  • Exomes 𝑓: 0.14 (16291 hom.)
• Consequence: COL18A1 NM_001379500.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.679
• Publications: 8 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).
• BP6: Variant 21-45473853-A-G is Benign according to our data. Variant chr21-45473853-A-G is described in ClinVar as Benign. ClinVar VariationId is 261885.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.462 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL18A1	NM_001379500.1	MANE Select	c.652-42A>G		intron	N/A	NP_001366429.1
	COL18A1	NM_130444.3		c.1897-42A>G		intron	N/A	NP_569711.2
	COL18A1	NM_030582.4		c.1192-42A>G		intron	N/A	NP_085059.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL18A1	ENST00000651438.1	MANE Select	c.652-42A>G		intron	N/A	ENSP00000498485.1
	COL18A1	ENST00000355480.10	TSL:1	c.1192-42A>G		intron	N/A	ENSP00000347665.5
	COL18A1	ENST00000359759.8	TSL:5	c.1897-42A>G		intron	N/A	ENSP00000352798.4

Frequencies

GnomAD3 genomes AF: 0.231 AC: 35083 AN: 151808 Hom.: 5819 Cov.: 32

Gnomad AFR AF: 0.468

Gnomad AMI AF: 0.151

Gnomad AMR AF: 0.163

Gnomad ASJ AF: 0.176

Gnomad EAS AF: 0.237

Gnomad SAS AF: 0.127

Gnomad FIN AF: 0.149

Gnomad MID AF: 0.203

Gnomad NFE AF: 0.127

Gnomad OTH AF: 0.210

GnomAD2 exomes AF: 0.163 AC: 26733 AN: 164418 AF XY: 0.159

Gnomad AFR exome AF: 0.477

Gnomad AMR exome AF: 0.150

Gnomad ASJ exome AF: 0.153

Gnomad EAS exome AF: 0.250

Gnomad FIN exome AF: 0.142

Gnomad NFE exome AF: 0.127

Gnomad OTH exome AF: 0.159

GnomAD4 exome AF: 0.142 AC: 195041 AN: 1373072 Hom.: 16291 Cov.: 25 AF XY: 0.141 AC XY: 95901 AN XY: 680524

African (AFR) AF: 0.487 AC: 15184 AN: 31184

American (AMR) AF: 0.149 AC: 5472 AN: 36816

Ashkenazi Jewish (ASJ) AF: 0.158 AC: 3956 AN: 24996

East Asian (EAS) AF: 0.215 AC: 7740 AN: 36066

South Asian (SAS) AF: 0.133 AC: 10521 AN: 79122

European-Finnish (FIN) AF: 0.147 AC: 7184 AN: 48852

Middle Eastern (MID) AF: 0.187 AC: 1025 AN: 5484

European-Non Finnish (NFE) AF: 0.128 AC: 134378 AN: 1053438

Other (OTH) AF: 0.168 AC: 9581 AN: 57114

GnomAD4 genome AF: 0.231 AC: 35149 AN: 151926 Hom.: 5834 Cov.: 32 AF XY: 0.230 AC XY: 17109 AN XY: 74268

African (AFR) AF: 0.468 AC: 19365 AN: 41390

American (AMR) AF: 0.163 AC: 2492 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.176 AC: 612 AN: 3468

East Asian (EAS) AF: 0.237 AC: 1220 AN: 5140

South Asian (SAS) AF: 0.129 AC: 618 AN: 4806

European-Finnish (FIN) AF: 0.149 AC: 1573 AN: 10582

Middle Eastern (MID) AF: 0.211 AC: 62 AN: 294

European-Non Finnish (NFE) AF: 0.127 AC: 8629 AN: 67942

Other (OTH) AF: 0.209 AC: 440 AN: 2108

Alfa AF: 0.173 Hom.: 581

Bravo AF: 0.243

Asia WGS AF: 0.195 AC: 678 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	0.93
DANN	Benign	0.62
PhyloP100		-0.68
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=16/84	disease causing

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: rs2236456; hg19: chr21-46893767; COSMIC: COSV62698237; COSMIC: COSV62698237;