21-45492744-G-GCCCGCCACTGCCCT

Variant names:

• chr21-45492744-G-GCCCGCCACTGCCCT
• rs11267376
• NM_001379500.1:c.2214+35_2214+36insCCACTGCCCTCCCG

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_001379500.1(COL18A1):​c.2214+35_2214+36insCCACTGCCCTCCCG variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.422 in 1,547,080 control chromosomes in the GnomAD database, including 144,183 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.49 (19652 hom., cov: 0)
  • Exomes 𝑓: 0.41 (124531 hom.)
• Consequence: COL18A1 NM_001379500.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.588
• Publications: 4 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 -16 ACMG points.

• BP6: Variant 21-45492744-G-GCCCGCCACTGCCCT is Benign according to our data. Variant chr21-45492744-G-GCCCGCCACTGCCCT is described in ClinVar as Benign. ClinVar VariationId is 261900.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.661 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.2214+35_2214+36insCCACTGCCCTCCCG		intron	N/A	NP_001366429.1
	COL18A1	NM_130444.3		c.3459+35_3459+36insCCACTGCCCTCCCG		intron	N/A	NP_569711.2
	COL18A1	NM_030582.4		c.2754+35_2754+36insCCACTGCCCTCCCG		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.2214+31_2214+32insCCCGCCACTGCCCT		intron	N/A	ENSP00000498485.1
	COL18A1	ENST00000355480.10	TSL:1	c.2754+31_2754+32insCCCGCCACTGCCCT		intron	N/A	ENSP00000347665.5
	COL18A1	ENST00000359759.8	TSL:5	c.3459+31_3459+32insCCCGCCACTGCCCT		intron	N/A	ENSP00000352798.4

Frequencies

GnomAD3 genomes AF: 0.495 AC: 75121 AN: 151830 Hom.: 19625 Cov.: 0

Gnomad AFR AF: 0.667

Gnomad AMI AF: 0.382

Gnomad AMR AF: 0.438

Gnomad ASJ AF: 0.509

Gnomad EAS AF: 0.468

Gnomad SAS AF: 0.453

Gnomad FIN AF: 0.451

Gnomad MID AF: 0.462

Gnomad NFE AF: 0.416

Gnomad OTH AF: 0.489

GnomAD4 exome AF: 0.414 AC: 578264 AN: 1395134 Hom.: 124531 Cov.: 28 AF XY: 0.416 AC XY: 290148 AN XY: 697304

African (AFR) AF: 0.680 AC: 21734 AN: 31960

American (AMR) AF: 0.415 AC: 18525 AN: 44610

Ashkenazi Jewish (ASJ) AF: 0.495 AC: 12683 AN: 25646

East Asian (EAS) AF: 0.455 AC: 17936 AN: 39414

South Asian (SAS) AF: 0.442 AC: 37565 AN: 84974

European-Finnish (FIN) AF: 0.405 AC: 18137 AN: 44742

Middle Eastern (MID) AF: 0.476 AC: 2070 AN: 4352

European-Non Finnish (NFE) AF: 0.400 AC: 424214 AN: 1061246

Other (OTH) AF: 0.437 AC: 25400 AN: 58190

GnomAD4 genome AF: 0.495 AC: 75189 AN: 151946 Hom.: 19652 Cov.: 0 AF XY: 0.496 AC XY: 36841 AN XY: 74266

African (AFR) AF: 0.667 AC: 27637 AN: 41424

American (AMR) AF: 0.437 AC: 6680 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.509 AC: 1766 AN: 3470

East Asian (EAS) AF: 0.468 AC: 2398 AN: 5122

South Asian (SAS) AF: 0.453 AC: 2181 AN: 4814

European-Finnish (FIN) AF: 0.451 AC: 4776 AN: 10594

Middle Eastern (MID) AF: 0.469 AC: 138 AN: 294

European-Non Finnish (NFE) AF: 0.416 AC: 28240 AN: 67940

Other (OTH) AF: 0.488 AC: 1025 AN: 2100

Alfa AF: 0.459 Hom.: 2737

Asia WGS AF: 0.465 AC: 1620 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.59
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs11267376; hg19: chr21-46912658; COSMIC: COSV107421614; COSMIC: COSV107421614;