chr21-45486713-C-T

Variant names:

• chr21-45486713-C-T
• rs2274808
• NM_001379500.1:c.1702-148C>T

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.1702-148C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.215 in 799,392 control chromosomes in the GnomAD database, including 19,379 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.19 (3012 hom., cov: 33)
  • Exomes 𝑓: 0.22 (16367 hom.)
• Consequence: COL18A1 NM_001379500.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.135
• Publications: 20 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=-0.87).
• BP6: Variant 21-45486713-C-T is Benign according to our data. Variant chr21-45486713-C-T is described in ClinVar as Benign. ClinVar VariationId is 1287312.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.1702-148C>T		intron	N/A	NP_001366429.1	P39060-2
	COL18A1	NM_130444.3		c.2947-148C>T		intron	N/A	NP_569711.2
	COL18A1	NM_030582.4		c.2242-148C>T		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.1702-148C>T		intron	N/A	ENSP00000498485.1	P39060-2
	COL18A1	ENST00000355480.10	TSL:1	c.2242-148C>T		intron	N/A	ENSP00000347665.5	P39060-1
	COL18A1	ENST00000359759.8	TSL:5	c.2947-148C>T		intron	N/A	ENSP00000352798.4	P39060-3

Frequencies

GnomAD3 genomes AF: 0.193 AC: 29438 AN: 152154 Hom.: 3012 Cov.: 33

Gnomad AFR AF: 0.115

Gnomad AMI AF: 0.0965

Gnomad AMR AF: 0.225

Gnomad ASJ AF: 0.256

Gnomad EAS AF: 0.137

Gnomad SAS AF: 0.182

Gnomad FIN AF: 0.207

Gnomad MID AF: 0.247

Gnomad NFE AF: 0.234

Gnomad OTH AF: 0.217

GnomAD4 exome AF: 0.221 AC: 142731 AN: 647120 Hom.: 16367 AF XY: 0.219 AC XY: 73063 AN XY: 333788

African (AFR) AF: 0.112 AC: 1696 AN: 15080

American (AMR) AF: 0.215 AC: 4456 AN: 20678

Ashkenazi Jewish (ASJ) AF: 0.263 AC: 4075 AN: 15490

East Asian (EAS) AF: 0.112 AC: 3335 AN: 29838

South Asian (SAS) AF: 0.178 AC: 9301 AN: 52348

European-Finnish (FIN) AF: 0.196 AC: 5956 AN: 30324

Middle Eastern (MID) AF: 0.266 AC: 695 AN: 2612

European-Non Finnish (NFE) AF: 0.237 AC: 106260 AN: 448404

Other (OTH) AF: 0.215 AC: 6957 AN: 32346

GnomAD4 genome AF: 0.193 AC: 29435 AN: 152272 Hom.: 3012 Cov.: 33 AF XY: 0.193 AC XY: 14403 AN XY: 74446

African (AFR) AF: 0.115 AC: 4763 AN: 41566

American (AMR) AF: 0.225 AC: 3438 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.256 AC: 890 AN: 3472

East Asian (EAS) AF: 0.138 AC: 712 AN: 5178

South Asian (SAS) AF: 0.182 AC: 882 AN: 4834

European-Finnish (FIN) AF: 0.207 AC: 2197 AN: 10610

Middle Eastern (MID) AF: 0.255 AC: 75 AN: 294

European-Non Finnish (NFE) AF: 0.234 AC: 15934 AN: 67990

Other (OTH) AF: 0.216 AC: 456 AN: 2114

Alfa AF: 0.197 Hom.: 2332

Bravo AF: 0.192

Asia WGS AF: 0.172 AC: 599 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	1.5
DANN	Benign	0.92
PhyloP100		-0.14
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: rs2274808; hg19: chr21-46906627;