rs2236457

Variant names:

• chr21-45474088-C-T
• rs2236457
• NM_001379500.1:c.738+107C>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.738+107C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.156 in 819,022 control chromosomes in the GnomAD database, including 12,685 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.22 (4811 hom., cov: 32)
  • Exomes 𝑓: 0.14 (7874 hom.)
• Consequence: COL18A1 NM_001379500.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.702
• Publications: 7 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=-0.93).
• BP6: Variant 21-45474088-C-T is Benign according to our data. Variant chr21-45474088-C-T is described in ClinVar as Benign. ClinVar VariationId is 1233011.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.407 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL18A1	NM_001379500.1	c.738+107C>T		intron_variant	Intron 4 of 41	ENST00000651438.1	NP_001366429.1
COL18A1	NM_130444.3	c.1983+107C>T		intron_variant	Intron 3 of 40		NP_569711.2
COL18A1	NM_030582.4	c.1278+107C>T		intron_variant	Intron 3 of 40		NP_085059.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL18A1	ENST00000651438.1	c.738+107C>T		intron_variant	Intron 4 of 41		NM_001379500.1	ENSP00000498485.1
COL18A1	ENST00000355480.10	c.1278+107C>T		intron_variant	Intron 3 of 40	1		ENSP00000347665.5
COL18A1	ENST00000359759.8	c.1983+107C>T		intron_variant	Intron 3 of 40	5		ENSP00000352798.4

Frequencies

GnomAD3 genomes AF: 0.215 AC: 32726 AN: 152024 Hom.: 4802 Cov.: 32

Gnomad AFR AF: 0.412

Gnomad AMI AF: 0.151

Gnomad AMR AF: 0.159

Gnomad ASJ AF: 0.177

Gnomad EAS AF: 0.237

Gnomad SAS AF: 0.128

Gnomad FIN AF: 0.147

Gnomad MID AF: 0.207

Gnomad NFE AF: 0.127

Gnomad OTH AF: 0.197

GnomAD4 exome AF: 0.143 AC: 95088 AN: 666880 Hom.: 7874 AF XY: 0.142 AC XY: 49108 AN XY: 346578

African (AFR) AF: 0.417 AC: 7407 AN: 17772

American (AMR) AF: 0.146 AC: 4802 AN: 32824

Ashkenazi Jewish (ASJ) AF: 0.157 AC: 2897 AN: 18504

East Asian (EAS) AF: 0.212 AC: 6810 AN: 32120

South Asian (SAS) AF: 0.133 AC: 7981 AN: 59876

European-Finnish (FIN) AF: 0.149 AC: 5478 AN: 36788

Middle Eastern (MID) AF: 0.184 AC: 771 AN: 4196

European-Non Finnish (NFE) AF: 0.124 AC: 53366 AN: 431026

Other (OTH) AF: 0.165 AC: 5576 AN: 33774

GnomAD4 genome AF: 0.215 AC: 32781 AN: 152142 Hom.: 4811 Cov.: 32 AF XY: 0.215 AC XY: 15979 AN XY: 74378

African (AFR) AF: 0.412 AC: 17094 AN: 41466

American (AMR) AF: 0.159 AC: 2426 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.177 AC: 613 AN: 3470

East Asian (EAS) AF: 0.237 AC: 1228 AN: 5178

South Asian (SAS) AF: 0.129 AC: 623 AN: 4822

European-Finnish (FIN) AF: 0.147 AC: 1562 AN: 10602

Middle Eastern (MID) AF: 0.212 AC: 62 AN: 292

European-Non Finnish (NFE) AF: 0.127 AC: 8622 AN: 67996

Other (OTH) AF: 0.196 AC: 413 AN: 2108

Alfa AF: 0.174 Hom.: 400

Bravo AF: 0.226

Asia WGS AF: 0.191 AC: 666 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

May 11, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.52
DANN	Benign	0.60
PhyloP100		-0.70
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: rs2236457; hg19: chr21-46894002; COSMIC: COSV62698525; COSMIC: COSV62698525;