rs769742294

chr1-207757204-T-G

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1_StrongPM2PP3_StrongPP5_Very_Strong

The NM_172351.3(CD46):c.286+2T>G variant causes a splice donor 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. 2/2 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

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: 2.69

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1

Splicing variant, NOT destroyed by nmd, known LOF gene, truncates exone, which is 0.16578484 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. No scorers claiming Benign.

PP5

Variant 1-207757204-T-G is Pathogenic according to our data. Variant chr1-207757204-T-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 505831.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-207757204-T-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CD46	NM_172351.3 linkuse as main transcript	c.286+2T>G		splice_donor_variant		ENST00000367042.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CD46	ENST00000367042.6 linkuse as main transcript	c.286+2T>G		splice_donor_variant		1	NM_172351.3	A2	P15529-11

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152184

Hom.:

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.0000521

AC:

AN:

249756

Hom.:

AF XY:

0.0000592

AC XY:

AN XY:

135152

show subpopulations

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 SAS 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.:

Cov.:

AF XY:

0.000127

AC XY:

AN XY:

726106

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000154

Gnomad4 OTH exome

AF:

0.0000829

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152184

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74344

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000882

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000670

Hom.:

Bravo

AF:

0.0000453

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ExAC

AF:

0.0000330

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000178

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Atypical hemolytic-uremic syndrome with MCP/CD46 anomaly

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	May 27, 2022	_x000D_ Criteria applied: PVS1, PM3_STR, PS4_SUP identified in patient with polygenic aHUS together with variant in CFH (ClinVar-ID: 1068249) -
Pathogenic, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Apr 27, 2020	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	May 02, 2022	- -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 06, 2021	PP1, PM3, PS4, PVS1 -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 12, 2024	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. -

Atypical hemolytic-uremic syndrome

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jul 28, 2017	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. -
Pathogenic, no assertion criteria provided	clinical testing	Sydney Genome Diagnostics, Children's Hospital Westmead	Oct 24, 2018	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. -

Familial Atypical Hemolytic-Uremic Syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Feb 07, 2024

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 v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.44

BayesDel_noAF

Benign

-0.49

Cadd

Pathogenic

Dann

Benign

0.83

Eigen

Uncertain

0.50

Eigen_PC

Benign

0.19

FATHMM_MKL

Uncertain

0.78

MutationTaster

Benign

1.0

D;D;D;D;D;D;D;D;D;D;D;D

GERP RS

2.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over