rs2838920

Variant names:

• chr21-45421483-G-A
• rs2838920
• ENST00000397787.5:n.1658C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000397787.5(COL18A1-AS1):​n.1658C>T variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.132 in 534,456 control chromosomes in the GnomAD database, including 5,777 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.16 (2490 hom., cov: 33)
  • Exomes 𝑓: 0.12 (3287 hom.)
• Consequence: COL18A1-AS1 ENST00000397787.5 non_coding_transcript_exon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.03
• Publications: 13 publications found

Genes affected

COL18A1-AS1 (HGNC:23132): (COL18A1 antisense RNA 1)

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.275 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL18A1	NM_001379500.1	c.106+16010G>A		intron_variant	Intron 2 of 41	ENST00000651438.1	NP_001366429.1
COL18A1-AS1	NR_027498.1	n.574C>T		non_coding_transcript_exon_variant	Exon 3 of 3
COL18A1-AS1	NR_028082.1	n.1658C>T		non_coding_transcript_exon_variant	Exon 3 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL18A1-AS1	ENST00000397787.5	n.1658C>T		non_coding_transcript_exon_variant	Exon 3 of 3	1
COL18A1-AS1	ENST00000485206.1	n.574C>T		non_coding_transcript_exon_variant	Exon 3 of 3	1
COL18A1	ENST00000651438.1	c.106+16010G>A		intron_variant	Intron 2 of 41		NM_001379500.1	ENSP00000498485.1

Frequencies

GnomAD3 genomes AF: 0.161 AC: 24485 AN: 152108 Hom.: 2488 Cov.: 33

Gnomad AFR AF: 0.279

Gnomad AMI AF: 0.0603

Gnomad AMR AF: 0.127

Gnomad ASJ AF: 0.137

Gnomad EAS AF: 0.257

Gnomad SAS AF: 0.131

Gnomad FIN AF: 0.126

Gnomad MID AF: 0.168

Gnomad NFE AF: 0.0994

Gnomad OTH AF: 0.160

GnomAD2 exomes AF: 0.136 AC: 34047 AN: 251026 AF XY: 0.132

Gnomad AFR exome AF: 0.282

Gnomad AMR exome AF: 0.128

Gnomad ASJ exome AF: 0.124

Gnomad EAS exome AF: 0.287

Gnomad FIN exome AF: 0.117

Gnomad NFE exome AF: 0.0990

Gnomad OTH exome AF: 0.122

GnomAD4 exome AF: 0.121 AC: 46283 AN: 382230 Hom.: 3287 Cov.: 0 AF XY: 0.121 AC XY: 26308 AN XY: 217608

African (AFR) AF: 0.277 AC: 2911 AN: 10514

American (AMR) AF: 0.128 AC: 4632 AN: 36298

Ashkenazi Jewish (ASJ) AF: 0.123 AC: 1442 AN: 11742

East Asian (EAS) AF: 0.279 AC: 3677 AN: 13176

South Asian (SAS) AF: 0.131 AC: 8742 AN: 66764

European-Finnish (FIN) AF: 0.117 AC: 3767 AN: 32112

Middle Eastern (MID) AF: 0.150 AC: 427 AN: 2848

European-Non Finnish (NFE) AF: 0.0963 AC: 18499 AN: 192058

Other (OTH) AF: 0.131 AC: 2186 AN: 16718

GnomAD4 genome AF: 0.161 AC: 24511 AN: 152226 Hom.: 2490 Cov.: 33 AF XY: 0.163 AC XY: 12098 AN XY: 74424

African (AFR) AF: 0.279 AC: 11590 AN: 41520

American (AMR) AF: 0.127 AC: 1947 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.137 AC: 474 AN: 3470

East Asian (EAS) AF: 0.257 AC: 1327 AN: 5160

South Asian (SAS) AF: 0.131 AC: 635 AN: 4832

European-Finnish (FIN) AF: 0.126 AC: 1338 AN: 10620

Middle Eastern (MID) AF: 0.163 AC: 48 AN: 294

European-Non Finnish (NFE) AF: 0.0994 AC: 6762 AN: 68004

Other (OTH) AF: 0.159 AC: 335 AN: 2112

Alfa AF: 0.126 Hom.: 3513

Bravo AF: 0.167

Asia WGS AF: 0.202 AC: 704 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.44
DANN	Benign	0.86
PhyloP100		-1.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs2838920; hg19: chr21-46841398; COSMIC: COSV67268553;