chr21-45486944-CCCCCCTGGG-C

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM4BP6BS2

The NM_001379500.1(COL18A1):c.1800_1808delTGGGCCCCC(p.Gly601_Pro603del) variant causes a disruptive inframe deletion change. The variant allele was found at a frequency of 0.000531 in 1,486,532 control chromosomes in the GnomAD database, including 5 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00098 ( 1 hom., cov: 33)

Exomes 𝑓: 0.00048 ( 4 hom. )

Consequence

COL18A1
NM_001379500.1 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: 4.83

Publications

2 publications found

Variant links:

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

COL18A1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -3 ACMG points.

PM4

Nonframeshift variant in NON repetitive region in NM_001379500.1.

BP6

Variant 21-45486944-CCCCCCTGGG-C is Benign according to our data. Variant chr21-45486944-CCCCCCTGGG-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 447115.

BS2

High Homozygotes in GnomAdExome4 at 4 AD,AR gene

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
COL18A1	NM_001379500.1	MANE Select	c.1800_1808delTGGGCCCCC	p.Gly601_Pro603del	disruptive_inframe_deletion	Exon 16 of 42	NP_001366429.1	P39060-2
COL18A1	NM_130444.3		c.3045_3053delTGGGCCCCC	p.Gly1016_Pro1018del	disruptive_inframe_deletion	Exon 15 of 41	NP_569711.2
COL18A1	NM_030582.4		c.2340_2348delTGGGCCCCC	p.Gly781_Pro783del	disruptive_inframe_deletion	Exon 15 of 41	NP_085059.2	A0AAG2UXZ5

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
COL18A1	ENST00000651438.1	MANE Select	c.1800_1808delTGGGCCCCC	p.Gly601_Pro603del	disruptive_inframe_deletion	Exon 16 of 42	ENSP00000498485.1	P39060-2
COL18A1	ENST00000355480.10	TSL:1	c.2340_2348delTGGGCCCCC	p.Gly781_Pro783del	disruptive_inframe_deletion	Exon 15 of 41	ENSP00000347665.5	P39060-1
COL18A1	ENST00000359759.8	TSL:5	c.3045_3053delTGGGCCCCC	p.Gly1016_Pro1018del	disruptive_inframe_deletion	Exon 15 of 41	ENSP00000352798.4	P39060-3

Frequencies

GnomAD3 genomes

AF:

0.000967

AC:

147

AN:

151956

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00218

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00507

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.000377

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000221

Gnomad OTH

AF:

0.00144

GnomAD2 exomes

AF:

0.000766

AC:

AN:

107000

AF XY:

0.000735

show subpopulations

Gnomad AFR exome

AF:

0.00186

Gnomad AMR exome

AF:

0.000232

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00615

Gnomad FIN exome

AF:

0.000331

Gnomad NFE exome

AF:

0.000141

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000480

AC:

641

AN:

1334458

Hom.:

AF XY:

0.000468

AC XY:

307

AN XY:

656280

show subpopulations

African (AFR)

AF:

0.00228

AC:

AN:

28976

American (AMR)

AF:

0.000256

AC:

AN:

27310

Ashkenazi Jewish (ASJ)

AF:

0.0000927

AC:

AN:

21576

East Asian (EAS)

AF:

0.00714

AC:

247

AN:

34610

South Asian (SAS)

AF:

0.000360

AC:

AN:

72124

European-Finnish (FIN)

AF:

0.000428

AC:

AN:

42030

Middle Eastern (MID)

AF:

0.000265

AC:

AN:

3778

European-Non Finnish (NFE)

AF:

0.000235

AC:

246

AN:

1048890

Other (OTH)

AF:

0.000508

AC:

AN:

55164

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

121

151

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000980

AC:

149

AN:

152074

Hom.:

Cov.:

AF XY:

0.00113

AC XY:

AN XY:

74352

show subpopulations

African (AFR)

AF:

0.00224

AC:

AN:

41500

American (AMR)

AF:

0.000327

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3470

East Asian (EAS)

AF:

0.00488

AC:

AN:

5118

South Asian (SAS)

AF:

0.000622

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.000377

AC:

AN:

10604

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000221

AC:

AN:

67946

Other (OTH)

AF:

0.00142

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00114

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (2)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

4.8

Mutation Taster

=148/52

polymorphism

(source)

Splicing

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over