21-45490313-C-G

Position:

• chr21-45490313-C-G

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_Strong BP7

The NM_001379500.1(COL18A1):​c.1998C>G​(p.Gly666Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000417 in 1,437,338 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 25)
  • Exomes 𝑓: 0.0000042 (0 hom.)
• Consequence: COL18A1 NM_001379500.1 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.998

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 Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP7: Synonymous conserved (PhyloP=-0.998 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL18A1	NM_001379500.1	c.1998C>G	p.Gly666Gly	synonymous_variant	20/42	ENST00000651438.1	NP_001366429.1
COL18A1	NM_130444.3	c.3243C>G	p.Gly1081Gly	synonymous_variant	19/41		NP_569711.2
COL18A1	NM_030582.4	c.2538C>G	p.Gly846Gly	synonymous_variant	19/41		NP_085059.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL18A1	ENST00000651438.1	c.1998C>G	p.Gly666Gly	synonymous_variant	20/42		NM_001379500.1	ENSP00000498485.1
COL18A1	ENST00000355480.10	c.2538C>G	p.Gly846Gly	synonymous_variant	19/41	1		ENSP00000347665.5
COL18A1	ENST00000359759.8	c.3243C>G	p.Gly1081Gly	synonymous_variant	19/41	5		ENSP00000352798.4
COL18A1	ENST00000342220.9	c.39C>G	p.Gly13Gly	synonymous_variant	1/23	2		ENSP00000339118.5

Frequencies

GnomAD3 genomes Cov.: 25

GnomAD3 exomes AF: 0.00000483 AC: 1 AN: 206834 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 112144

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000647

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000417 AC: 6 AN: 1437338 Hom.: 0 Cov.: 32 AF XY: 0.00000281 AC XY: 2 AN XY: 712706

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000129

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000168

GnomAD4 genome Cov.: 25

Alfa AF: 0.0000165 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	6.4
DANN	Benign	0.86
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		2.9

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: rs62000963; hg19: chr21-46910227;