rs2236457

Positions:

• chr21-45474088-C-T

Variant summary

Our verdict is Benign. Variant got -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

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 -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 id 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/exons	MANE	Protein	UniProt
COL18A1	NM_001379500.1	c.738+107C>T		intron_variant		ENST00000651438.1	NP_001366429.1
COL18A1	NM_030582.4	c.1278+107C>T		intron_variant			NP_085059.2
COL18A1	NM_130444.3	c.1983+107C>T		intron_variant			NP_569711.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL18A1	ENST00000651438.1	c.738+107C>T		intron_variant			NM_001379500.1	ENSP00000498485
COL18A1	ENST00000355480.10	c.1278+107C>T		intron_variant		1		ENSP00000347665
COL18A1	ENST00000359759.8	c.1983+107C>T		intron_variant		5		ENSP00000352798	P1

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

Gnomad4 AFR exome AF: 0.417

Gnomad4 AMR exome AF: 0.146

Gnomad4 ASJ exome AF: 0.157

Gnomad4 EAS exome AF: 0.212

Gnomad4 SAS exome AF: 0.133

Gnomad4 FIN exome AF: 0.149

Gnomad4 NFE exome AF: 0.124

Gnomad4 OTH exome AF: 0.165

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

Gnomad4 AFR AF: 0.412

Gnomad4 AMR AF: 0.159

Gnomad4 ASJ AF: 0.177

Gnomad4 EAS AF: 0.237

Gnomad4 SAS AF: 0.129

Gnomad4 FIN AF: 0.147

Gnomad4 NFE AF: 0.127

Gnomad4 OTH AF: 0.196

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

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 11, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.52
DANN	Benign	0.60

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: rs2236457; hg19: chr21-46894002; COSMIC: COSV62698525; COSMIC: COSV62698525;