rs79980197

Variant names:

• chr21-45491274-C-G
• rs79980197
• NM_001379500.1:c.2117C>G

Your query was ambiguous. Multiple possible variants found:

• chr21-45491274-C-G
• chr21-45491274-C-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.2117C>G​(p.Pro706Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0788 in 1,612,096 control chromosomes in the GnomAD database, including 5,643 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P706L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.071 (494 hom., cov: 32)
  • Exomes 𝑓: 0.080 (5149 hom.)
• Consequence: COL18A1 NM_001379500.1 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 4.57
• 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: 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 (MetaRNN=0.0020926893).
• BP6: Variant 21-45491274-C-G is Benign according to our data. Variant chr21-45491274-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 261898.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.111 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.2117C>G	p.Pro706Arg	missense	Exon 22 of 42	NP_001366429.1
	COL18A1	NM_130444.3		c.3362C>G	p.Pro1121Arg	missense	Exon 21 of 41	NP_569711.2
	COL18A1	NM_030582.4		c.2657C>G	p.Pro886Arg	missense	Exon 21 of 41	NP_085059.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL18A1	ENST00000651438.1	MANE Select	c.2117C>G	p.Pro706Arg	missense	Exon 22 of 42	ENSP00000498485.1
	COL18A1	ENST00000355480.10	TSL:1	c.2657C>G	p.Pro886Arg	missense	Exon 21 of 41	ENSP00000347665.5
	COL18A1	ENST00000359759.8	TSL:5	c.3362C>G	p.Pro1121Arg	missense	Exon 21 of 41	ENSP00000352798.4

Frequencies

GnomAD3 genomes AF: 0.0708 AC: 10765 AN: 152120 Hom.: 496 Cov.: 32

Gnomad AFR AF: 0.0325

Gnomad AMI AF: 0.120

Gnomad AMR AF: 0.0428

Gnomad ASJ AF: 0.0637

Gnomad EAS AF: 0.0711

Gnomad SAS AF: 0.119

Gnomad FIN AF: 0.170

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.0816

Gnomad OTH AF: 0.0599

GnomAD2 exomes AF: 0.0830 AC: 20339 AN: 245174 AF XY: 0.0871

Gnomad AFR exome AF: 0.0336

Gnomad AMR exome AF: 0.0292

Gnomad ASJ exome AF: 0.0726

Gnomad EAS exome AF: 0.0766

Gnomad FIN exome AF: 0.157

Gnomad NFE exome AF: 0.0847

Gnomad OTH exome AF: 0.0772

GnomAD4 exome AF: 0.0796 AC: 116225 AN: 1459858 Hom.: 5149 Cov.: 33 AF XY: 0.0812 AC XY: 58956 AN XY: 726214

African (AFR) AF: 0.0340 AC: 1138 AN: 33472

American (AMR) AF: 0.0298 AC: 1333 AN: 44688

Ashkenazi Jewish (ASJ) AF: 0.0706 AC: 1844 AN: 26110

East Asian (EAS) AF: 0.0500 AC: 1983 AN: 39682

South Asian (SAS) AF: 0.119 AC: 10275 AN: 86224

European-Finnish (FIN) AF: 0.146 AC: 7595 AN: 52026

Middle Eastern (MID) AF: 0.0684 AC: 394 AN: 5758

European-Non Finnish (NFE) AF: 0.0786 AC: 87411 AN: 1111580

Other (OTH) AF: 0.0705 AC: 4252 AN: 60318

GnomAD4 genome AF: 0.0707 AC: 10769 AN: 152238 Hom.: 494 Cov.: 32 AF XY: 0.0756 AC XY: 5626 AN XY: 74434

African (AFR) AF: 0.0326 AC: 1354 AN: 41568

American (AMR) AF: 0.0427 AC: 654 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.0637 AC: 221 AN: 3470

East Asian (EAS) AF: 0.0710 AC: 367 AN: 5166

South Asian (SAS) AF: 0.119 AC: 575 AN: 4826

European-Finnish (FIN) AF: 0.170 AC: 1806 AN: 10612

Middle Eastern (MID) AF: 0.0442 AC: 13 AN: 294

European-Non Finnish (NFE) AF: 0.0816 AC: 5544 AN: 67974

Other (OTH) AF: 0.0598 AC: 126 AN: 2108

Alfa AF: 0.0627 Hom.: 131

Bravo AF: 0.0589

ESP6500AA AF: 0.0326 AC: 125

ESP6500EA AF: 0.0726 AC: 594

ExAC AF: 0.0833 AC: 9991

Asia WGS AF: 0.0880 AC: 308 AN: 3478

EpiCase AF: 0.0766

EpiControl AF: 0.0792

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	3	Knobloch syndrome (3)
-	-	1	Hereditary glaucoma, primary closed-angle (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Uncertain	-0.060
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.64	D
Eigen	Benign	0.18
Eigen_PC	Benign	0.051
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.81	T
MetaRNN	Benign	0.0021	T
MetaSVM	Benign	-0.34	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		4.6
PrimateAI	Uncertain	0.53	T
PROVEAN	Pathogenic	-5.7	D
REVEL	Uncertain	0.43
Sift	Benign	0.094	T
Sift4G	Benign	0.17	T
Polyphen		1.0	D
Vest4		0.33
MPC		0.42
ClinPred		0.033	T
GERP RS		3.9
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		2.9
Varity_R		0.28
gMVP		0.24
Mutation Taster		=96/4	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs79980197; hg19: chr21-46911188; COSMIC: COSV60590114; COSMIC: COSV60590114;