rs2236474

Positions:

• chr21-45487528-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001379500.1(COL18A1):​c.1896+19C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000761 in 1,612,084 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0011 (5 hom., cov: 33)
  • Exomes 𝑓: 0.00072 (16 hom.)
• Consequence: COL18A1 NM_001379500.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.58

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=-0.89).
• BP6: Variant 21-45487528-C-T is Benign according to our data. Variant chr21-45487528-C-T is described in ClinVar as [Benign]. Clinvar id is 1164947.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-45487528-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00113 (172/152230) while in subpopulation EAS AF= 0.0254 (131/5166). AF 95% confidence interval is 0.0218. There are 5 homozygotes in gnomad4. There are 92 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 5 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL18A1	NM_001379500.1	c.1896+19C>T		intron_variant		ENST00000651438.1	NP_001366429.1
COL18A1	NM_030582.4	c.2436+19C>T		intron_variant			NP_085059.2
COL18A1	NM_130444.3	c.3141+19C>T		intron_variant			NP_569711.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL18A1	ENST00000651438.1	c.1896+19C>T		intron_variant			NM_001379500.1	ENSP00000498485
COL18A1	ENST00000355480.10	c.2436+19C>T		intron_variant		1		ENSP00000347665
COL18A1	ENST00000359759.8	c.3141+19C>T		intron_variant		5		ENSP00000352798	P1

Frequencies

GnomAD3 genomes AF: 0.00112 AC: 171 AN: 152112 Hom.: 5 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00164

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0253

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00192

GnomAD3 exomes AF: 0.00184 AC: 456 AN: 247480 Hom.: 4 AF XY: 0.00169 AC XY: 227 AN XY: 134640

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0239

Gnomad SAS exome AF: 0.000294

Gnomad FIN exome AF: 0.0000976

Gnomad NFE exome AF: 0.0000889

Gnomad OTH exome AF: 0.000829

GnomAD4 exome AF: 0.000722 AC: 1054 AN: 1459854 Hom.: 16 Cov.: 33 AF XY: 0.000733 AC XY: 532 AN XY: 726238

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0224

Gnomad4 SAS exome AF: 0.000383

Gnomad4 FIN exome AF: 0.000174

Gnomad4 NFE exome AF: 0.0000324

Gnomad4 OTH exome AF: 0.00144

GnomAD4 genome AF: 0.00113 AC: 172 AN: 152230 Hom.: 5 Cov.: 33 AF XY: 0.00124 AC XY: 92 AN XY: 74440

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00163

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0254

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.000359 Hom.: 0

Bravo AF: 0.00109

Asia WGS AF: 0.00953 AC: 34 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	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 28, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	5.9
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: rs2236474; hg19: chr21-46907442; COSMIC: COSV60590552; COSMIC: COSV60590552;