chr21-45492744-G-GCCCGCCACTGCCCT

Position:

• chr21-45492744-G-GCCCGCCACTGCCCT

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_001379500.1(COL18A1):​c.2214+35_2214+36insCCACTGCCCTCCCG variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.422 in 1,547,080 control chromosomes in the GnomAD database, including 144,183 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.49 (19652 hom., cov: 0)
  • Exomes 𝑓: 0.41 (124531 hom.)
• Consequence: COL18A1 NM_001379500.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.588

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 -16 ACMG points.

• BP6: Variant 21-45492744-G-GCCCGCCACTGCCCT is Benign according to our data. Variant chr21-45492744-G-GCCCGCCACTGCCCT is described in ClinVar as [Benign]. Clinvar id is 261900.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.661 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL18A1	NM_001379500.1	c.2214+35_2214+36insCCACTGCCCTCCCG		intron_variant		ENST00000651438.1	NP_001366429.1
COL18A1	NM_030582.4	c.2754+35_2754+36insCCACTGCCCTCCCG		intron_variant			NP_085059.2
COL18A1	NM_130444.3	c.3459+35_3459+36insCCACTGCCCTCCCG		intron_variant			NP_569711.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL18A1	ENST00000651438.1	c.2214+35_2214+36insCCACTGCCCTCCCG		intron_variant			NM_001379500.1	ENSP00000498485
COL18A1	ENST00000355480.10	c.2754+35_2754+36insCCACTGCCCTCCCG		intron_variant		1		ENSP00000347665
COL18A1	ENST00000342220.9	c.255+35_255+36insCCACTGCCCTCCCG		intron_variant		2		ENSP00000339118
COL18A1	ENST00000359759.8	c.3459+35_3459+36insCCACTGCCCTCCCG		intron_variant		5		ENSP00000352798	P1

Frequencies

GnomAD3 genomes AF: 0.495 AC: 75121 AN: 151830 Hom.: 19625 Cov.: 0

Gnomad AFR AF: 0.667

Gnomad AMI AF: 0.382

Gnomad AMR AF: 0.438

Gnomad ASJ AF: 0.509

Gnomad EAS AF: 0.468

Gnomad SAS AF: 0.453

Gnomad FIN AF: 0.451

Gnomad MID AF: 0.462

Gnomad NFE AF: 0.416

Gnomad OTH AF: 0.489

GnomAD4 exome AF: 0.414 AC: 578264 AN: 1395134 Hom.: 124531 Cov.: 28 AF XY: 0.416 AC XY: 290148 AN XY: 697304

Gnomad4 AFR exome AF: 0.680

Gnomad4 AMR exome AF: 0.415

Gnomad4 ASJ exome AF: 0.495

Gnomad4 EAS exome AF: 0.455

Gnomad4 SAS exome AF: 0.442

Gnomad4 FIN exome AF: 0.405

Gnomad4 NFE exome AF: 0.400

Gnomad4 OTH exome AF: 0.437

GnomAD4 genome AF: 0.495 AC: 75189 AN: 151946 Hom.: 19652 Cov.: 0 AF XY: 0.496 AC XY: 36841 AN XY: 74266

Gnomad4 AFR AF: 0.667

Gnomad4 AMR AF: 0.437

Gnomad4 ASJ AF: 0.509

Gnomad4 EAS AF: 0.468

Gnomad4 SAS AF: 0.453

Gnomad4 FIN AF: 0.451

Gnomad4 NFE AF: 0.416

Gnomad4 OTH AF: 0.488

Alfa AF: 0.459 Hom.: 2737

Asia WGS AF: 0.465 AC: 1620 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 20, 2021

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs11267376; hg19: chr21-46912658;