1-207757204-T-G

Variant names:

• chr1-207757204-T-G
• rs769742294
• NM_172351.3:c.286+2T>G

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1_Strong PP5_Very_Strong

The NM_172351.3(CD46):​c.286+2T>G variant causes a splice donor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000115 in 1,611,488 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00012 (0 hom.)
• Consequence: CD46 NM_172351.3 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10
• Conservation: PhyloP100: 2.69
• Publications: 11 publications found

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]

CD46 Gene-Disease associations (from GenCC):

• atypical hemolytic-uremic syndrome with MCP/CD46 anomaly

  Inheritance: AD, AR, SD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, Ambry Genetics

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.16666667 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• PP5: Variant 1-207757204-T-G is Pathogenic according to our data. Variant chr1-207757204-T-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 505831.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_172351.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CD46	NM_172351.3	MANE Select	c.286+2T>G		splice_donor intron	N/A	NP_758861.1
	CD46	NM_172359.3		c.286+2T>G		splice_donor intron	N/A	NP_758869.1
	CD46	NM_002389.4		c.286+2T>G		splice_donor intron	N/A	NP_002380.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CD46	ENST00000367042.6	TSL:1 MANE Select	c.286+2T>G		splice_donor intron	N/A	ENSP00000356009.1
	CD46	ENST00000322875.8	TSL:1	c.286+2T>G		splice_donor intron	N/A	ENSP00000313875.4
	CD46	ENST00000358170.6	TSL:1	c.286+2T>G		splice_donor intron	N/A	ENSP00000350893.2

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152184 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000521 AC: 13 AN: 249756 AF XY: 0.0000592

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000106

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000123 AC: 179 AN: 1459304 Hom.: 0 Cov.: 31 AF XY: 0.000127 AC XY: 92 AN XY: 726106

African (AFR) AF: 0.0000299 AC: 1 AN: 33446

American (AMR) AF: 0.0000447 AC: 2 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26118

East Asian (EAS) AF: 0.00 AC: 0 AN: 39680

South Asian (SAS) AF: 0.00 AC: 0 AN: 86232

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52204

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000154 AC: 171 AN: 1110796

Other (OTH) AF: 0.0000829 AC: 5 AN: 60338

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152184 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74344

African (AFR) AF: 0.00 AC: 0 AN: 41436

American (AMR) AF: 0.00 AC: 0 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68040

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.0000517 Hom.: 0

Bravo AF: 0.0000453

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ExAC AF: 0.0000330 AC: 4

EpiCase AF: 0.0000545

EpiControl AF: 0.000178

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Atypical hemolytic-uremic syndrome with MCP/CD46 anomaly Pathogenic:4

Apr 27, 2020

Johns Hopkins Genomics, Johns Hopkins University

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This CD46 variant (rs769742294) is rare (<0.1%) in a large population dataset (gnomAD: 13/249756 total alleles; 0.005205%; no homozygotes). It has been previously reported in individuals with aHUS with incomplete penetrance. This variant destroys a canonical splice donor site and is predicted to affect normal exon 2 splicing. A single submitter in ClinVar classifies this variant as likely pathogenic. We consider it to be pathogenic.

Feb 17, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jun 19, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

May 27, 2022

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

_x000D_ Criteria applied: PVS1, PM3_STR, PS4_SUP identified in patient with polygenic aHUS together with variant in CFH (ClinVar-ID: 1068249)

Atypical hemolytic-uremic syndrome Pathogenic:3

Oct 24, 2018

Sydney Genome Diagnostics, Children's Hospital Westmead

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

This patient is heterozygous for a known pathogenic variant, c.286+2T>G, in the CD46 gene. In silico analysis (using Alamut visual v2.6) predicts this variant to abolish the consensus splice donor site at c.286, resulting in the skipping of exon 2. This variant in the heterozygote form has been reported in a patient with end-stage renal disease (ESRD) who developed atypical haemolytic uremic syndrome (aHUS) following renal transplantation from her asymptomatic mother who was also heterozygote for the variant (Alberti et al 2013 Am J Transplant 13:2201-2206). This variant, in both heterozygote and homozygote form, has been reported in patients who developed aHUS after a trigger, such as S. flexneri diarrhoeal illness or dengue shock syndrome (Brocklebank et al 2014 Clin Kidney J 7:286-288; Bhatia et al 2015 Pediatr Nephrol Aug 26). However, the latter paper also reported this variant, in both heterozygote and homozygote form, in asymptomatic individuals who were 50 to 100% deficient of CD46.

Jul 28, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.286+2T>G (NM_002389.4 c.286+2T>G) variant in CD46 has been previously repo rted in at least 4 heterozygous, 1 compound heterozygous, and 3 homozygous indiv iduals with atypical hemolytic uremic syndrome, and segregated with disease in o ne homozygous sibling (Fremeaux-Bacci 2006, Saunders 2007, Maga 2010, Bresin 201 3, Alberti 2013, Brocklebank 2014, Bhatia 2015, Phillips 2016, Sheerin 2016, and Besbas 2017, and Bhatia 2015). This variant occurs in the invariant region (+/ - 1,2) of the splice consensus sequence and has been demonstrated to impact spli cing (Fremeaux-Bacci 2006). It has been identified in 0.01% (11/111554) of Europ ean chromosomes by the Genome Aggregation Database (gnomAD, http://gnomAD.broadi nstitute.org; dbSNP rs769742294). Available data suggests that this variant is i nherited in an autosomal dominant manner with incomplete penetrance, and milder phenotype in heterozygotes and more severe, earlier-onset presentation in homozy gotes. In summary, the c.286+2T>C variant is likely pathogenic for atypical hem olytic uremic syndrome based upon observations in affected individuals and predi cted impact on the protein, though it may show reduced penetrance.

Oct 02, 2025

Genomenon, Inc, Genomenon, Inc

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

CD46 c.286+2T>G is a canonical splice variant located in the donor splice region in intron 2. This variant has been observed in at least one proband affected with atypical hemolytic-uremic syndrome (PMID:33224962;16762990;17617869;29644059). The variant was found to segregate with disease in at least one affected family (PMID:26307634;21906045). At least one splicing study identified that this variant results in aberrant splicing (PMID:33224962;16762990;17617869). It is absent or not present at a significant frequency in gnomAD. In conclusion, we classify CD46 c.286+2T>G as a pathogenic variant.

not provided Pathogenic:2

Jan 12, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects a donor splice site in intron 2 of the CD46 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in CD46 are known to be pathogenic (PMID: 16621965, 23431077). This variant is present in population databases (rs769742294, gnomAD 0.01%). Disruption of this splice site has been observed in individual(s) with hemolytic uremic syndrome (PMID: 16762990, 23431077, 26307634, 26559391). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 505831). Studies have shown that disruption of this splice site alters CD46 gene expression (PMID: 24944786, 26559391). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.

Mar 07, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP1, PM3, PS4, PVS1_strong

Familial Atypical Hemolytic-Uremic Syndrome Pathogenic:1

Feb 07, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: CD46 c.286+2T>G is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 5' splicing donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing, resulting in the deletion of 144 bp in exon 2 (Fremeaux-Bacchi_2006). The variant allele was found at a frequency of 5.2e-05 in 249756 control chromosomes (gnomAD). c.286+2T>G has been reported in the literature in multiple individuals affected with Genetic Atypical Hemolytic Uremic Syndrome, both in the homozygous state and in heterozygous individuals with incomplete penetrance (Fremeaux-Bacchi_2006, Khandelwal_CD46_CKJ_2018). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 16762990, 29644059). ClinVar contains an entry for this variant (Variation ID: 505831). Based on the evidence outlined above, the variant was classified as pathogenic.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Benign	-0.49
CADD	Pathogenic	32
DANN	Benign	0.83
Eigen	Uncertain	0.50
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.78	D
PhyloP100		2.7
GERP RS		2.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.78
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.74		Position offset: 2
DS_DL_spliceai		1.0		Position offset: -2

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

Other links and lift over

dbSNP: rs769742294; hg19: chr1-207930549;