rs11267376

Positions:

• chr21-45492744-G-GCCCGCCTCTGCCCT
• chr21-45492744-G-GCCCGCCACTGCCCT
• chr21-45492744-G-GCCCGTCACTGCCCT

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001379500.1(COL18A1):​c.2214+35_2214+36insCCTCTGCCCTCCCG variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000715 in 1,399,388 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 0)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: COL18A1 NM_001379500.1 intron
• Clinical Significance: Not reported in ClinVar
• 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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL18A1	NM_001379500.1	c.2214+35_2214+36insCCTCTGCCCTCCCG		intron_variant		ENST00000651438.1	NP_001366429.1
COL18A1	NM_030582.4	c.2754+35_2754+36insCCTCTGCCCTCCCG		intron_variant			NP_085059.2
COL18A1	NM_130444.3	c.3459+35_3459+36insCCTCTGCCCTCCCG		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+36insCCTCTGCCCTCCCG		intron_variant			NM_001379500.1	ENSP00000498485
COL18A1	ENST00000355480.10	c.2754+35_2754+36insCCTCTGCCCTCCCG		intron_variant		1		ENSP00000347665
COL18A1	ENST00000342220.9	c.255+35_255+36insCCTCTGCCCTCCCG		intron_variant		2		ENSP00000339118
COL18A1	ENST00000359759.8	c.3459+35_3459+36insCCTCTGCCCTCCCG		intron_variant		5		ENSP00000352798	P1

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD4 exome AF: 7.15e-7 AC: 1 AN: 1399388 Hom.: 0 Cov.: 28 AF XY: 0.00000143 AC XY: 1 AN XY: 699234

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000118

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 0

ClinVar

Not reported in ClinVar

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;