1-207761243-TT-G

Position:

• chr1-207761243-TT-G

Variant summary

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

The NM_172351.3(CD46):​c.476-6_476-5delinsG variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: CD46 NM_172351.3 splice_region, splice_polypyrimidine_tract, intron
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 0.908

Genes affected

CD46 (HGNC:6953): (CD46 molecule) The protein encoded by this gene is a type I membrane protein and is a regulatory part of the complement system. The encoded protein has cofactor activity for inactivation of complement components C3b and C4b by serum factor I, which protects the host cell from damage by complement. In addition, the encoded protein can act as a receptor for the Edmonston strain of measles virus, human herpesvirus-6, and type IV pili of pathogenic Neisseria. Finally, the protein encoded by this gene may be involved in the fusion of the spermatozoa with the oocyte during fertilization. Mutations at this locus have been associated with susceptibility to hemolytic uremic syndrome. Alternatively spliced transcript variants encoding different isoforms have been described. [provided by RefSeq, Jun 2010]

MIR29B2CHG (HGNC:32018): (MIR29B2 and MIR29C host gene)

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
CD46	NM_172351.3	c.476-6_476-5delinsG		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000367042.6	NP_758861.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CD46	ENST00000367042.6	c.476-6_476-5delinsG		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_172351.3	ENSP00000356009	A2
MIR29B2CHG	ENST00000710901.1	n.2407_2408delinsC		non_coding_transcript_exon_variant	6/6

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

Atypical hemolytic-uremic syndrome with MCP/CD46 anomaly Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 18, 2022

- -

Atypical hemolytic-uremic syndrome Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Sydney Genome Diagnostics, Children's Hospital Westmead

Feb 22, 2018

This patient is heterozygous for the c.476-6_476-5delinsG variant in the CD46 gene. To our knowledge, this variant has not been previously reported in the literature or any disease specific databases. In silico analysis of pathogenicity (through Alamut Visual v.2.8.1) predicts that this variant may affect splicing. This variant is considered to be a variant of uncertain clinical significance (VOUS) according to the ACMG guidelines. -

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: rs1656165500; hg19: chr1-207934588;