rs2838913

Positions:

• chr21-45417794-A-G
• chr21-45417794-A-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001379500.1(COL18A1):​c.106+12321A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.705 in 152,158 control chromosomes in the GnomAD database, including 37,989 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 0.70 (37989 hom., cov: 33)
• Consequence: COL18A1 NM_001379500.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0870

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.839 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL18A1	NM_001379500.1	c.106+12321A>G		intron_variant		ENST00000651438.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL18A1	ENST00000651438.1	c.106+12321A>G		intron_variant			NM_001379500.1

Frequencies

GnomAD3 genomes AF: 0.705 AC: 107163 AN: 152040 Hom.: 37960 Cov.: 33

Gnomad AFR AF: 0.656

Gnomad AMI AF: 0.789

Gnomad AMR AF: 0.732

Gnomad ASJ AF: 0.736

Gnomad EAS AF: 0.859

Gnomad SAS AF: 0.742

Gnomad FIN AF: 0.771

Gnomad MID AF: 0.726

Gnomad NFE AF: 0.701

Gnomad OTH AF: 0.715

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.705 AC: 107246 AN: 152158 Hom.: 37989 Cov.: 33 AF XY: 0.712 AC XY: 52984 AN XY: 74374

Gnomad4 AFR AF: 0.656

Gnomad4 AMR AF: 0.733

Gnomad4 ASJ AF: 0.736

Gnomad4 EAS AF: 0.860

Gnomad4 SAS AF: 0.743

Gnomad4 FIN AF: 0.771

Gnomad4 NFE AF: 0.701

Gnomad4 OTH AF: 0.711

Alfa AF: 0.705 Hom.: 44128

Bravo AF: 0.699

Asia WGS AF: 0.777 AC: 2701 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	0.30
DANN	Benign	0.48
RBP_binding_hub_radar		0.77
RBP_regulation_power_radar		1.9

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs2838913; hg19: chr21-46837709; COSMIC: COSV67268475; COSMIC: COSV67268475;