rs2236472

Positions:

• chr21-45483498-C-T
• chr21-45483498-C-G

Variant summary

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

The NM_001379500.1(COL18A1):​c.1701+677C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.194 in 151,972 control chromosomes in the GnomAD database, including 3,000 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 0.19 (3000 hom., cov: 33)
• Consequence: COL18A1 NM_001379500.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.279

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=-0.96).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.231 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL18A1	NM_001379500.1	c.1701+677C>T		intron_variant		ENST00000651438.1	NP_001366429.1
COL18A1	NM_030582.4	c.2241+677C>T		intron_variant			NP_085059.2
COL18A1	NM_130444.3	c.2946+677C>T		intron_variant			NP_569711.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL18A1	ENST00000651438.1	c.1701+677C>T		intron_variant			NM_001379500.1	ENSP00000498485
COL18A1	ENST00000355480.10	c.2241+677C>T		intron_variant		1		ENSP00000347665
COL18A1	ENST00000359759.8	c.2946+677C>T		intron_variant		5		ENSP00000352798	P1

Frequencies

GnomAD3 genomes AF: 0.194 AC: 29419 AN: 151852 Hom.: 3000 Cov.: 33

Gnomad AFR AF: 0.116

Gnomad AMI AF: 0.0965

Gnomad AMR AF: 0.225

Gnomad ASJ AF: 0.256

Gnomad EAS AF: 0.140

Gnomad SAS AF: 0.183

Gnomad FIN AF: 0.207

Gnomad MID AF: 0.250

Gnomad NFE AF: 0.234

Gnomad OTH AF: 0.216

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

GnomAD4 genome AF: 0.194 AC: 29422 AN: 151972 Hom.: 3000 Cov.: 33 AF XY: 0.194 AC XY: 14399 AN XY: 74264

Gnomad4 AFR AF: 0.116

Gnomad4 AMR AF: 0.225

Gnomad4 ASJ AF: 0.256

Gnomad4 EAS AF: 0.141

Gnomad4 SAS AF: 0.183

Gnomad4 FIN AF: 0.207

Gnomad4 NFE AF: 0.234

Gnomad4 OTH AF: 0.214

Alfa AF: 0.229 Hom.: 5072

Bravo AF: 0.192

Asia WGS AF: 0.171 AC: 596 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	5.3
DANN	Benign	0.48
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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

Publications

LitVar

Other links and lift over

dbSNP: rs2236472; hg19: chr21-46903412; COSMIC: COSV62699813;