rs12126088

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_172351.3(CD46):c.417A>G(p.Leu139Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00718 in 1,595,512 control chromosomes in the GnomAD database, including 51 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0057 ( 3 hom., cov: 33)

Exomes 𝑓: 0.0073 ( 48 hom. )

Consequence

CD46
NM_172351.3 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -2.17

Publications

6 publications found

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 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

CD46 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.86).

BP6

Variant 1-207759666-A-G is Benign according to our data. Variant chr1-207759666-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 522216.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-2.17 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00574 (875/152346) while in subpopulation NFE AF = 0.00853 (580/68030). AF 95% confidence interval is 0.00795. There are 3 homozygotes in GnomAd4. There are 429 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 3 AD,AR,SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CD46	NM_172351.3 link	c.417A>G	p.Leu139Leu	synonymous_variant	Exon 4 of 13	ENST00000367042.6	NP_758861.1	P15529-11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CD46	ENST00000367042.6 link	c.417A>G	p.Leu139Leu	synonymous_variant	Exon 4 of 13	1	NM_172351.3	ENSP00000356009.1		P15529-11

Frequencies

GnomAD3 genomes

AF:

0.00575

AC:

875

AN:

152228

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00543

Gnomad ASJ

AF:

0.0225

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00145

Gnomad FIN

AF:

0.00612

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.00852

Gnomad OTH

AF:

0.00334

GnomAD2 exomes

AF:

0.00666

AC:

1663

AN:

249636

AF XY:

0.00679

show subpopulations

Gnomad AFR exome

AF:

0.00107

Gnomad AMR exome

AF:

0.00395

Gnomad ASJ exome

AF:

0.0184

Gnomad EAS exome

AF:

0.000109

Gnomad FIN exome

AF:

0.00574

Gnomad NFE exome

AF:

0.00960

Gnomad OTH exome

AF:

0.00905

GnomAD4 exome

AF:

0.00733

AC:

10576

AN:

1443166

Hom.:

Cov.:

AF XY:

0.00725

AC XY:

5210

AN XY:

719014

show subpopulations

African (AFR)

AF:

0.000785

AC:

AN:

33132

American (AMR)

AF:

0.00401

AC:

179

AN:

44636

Ashkenazi Jewish (ASJ)

AF:

0.0176

AC:

457

AN:

25978

East Asian (EAS)

AF:

0.000101

AC:

AN:

39506

South Asian (SAS)

AF:

0.00199

AC:

171

AN:

85734

European-Finnish (FIN)

AF:

0.00658

AC:

351

AN:

53360

Middle Eastern (MID)

AF:

0.00575

AC:

AN:

5740

European-Non Finnish (NFE)

AF:

0.00816

AC:

8943

AN:

1095318

Other (OTH)

AF:

0.00689

AC:

412

AN:

59762

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

443

886

1328

1771

2214

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

330

660

990

1320

1650

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00574

AC:

875

AN:

152346

Hom.:

Cov.:

AF XY:

0.00576

AC XY:

429

AN XY:

74500

show subpopulations

African (AFR)

AF:

0.00120

AC:

AN:

41576

American (AMR)

AF:

0.00542

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.0225

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5192

South Asian (SAS)

AF:

0.00166

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00612

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00853

AC:

580

AN:

68030

Other (OTH)

AF:

0.00331

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

127

169

211

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00862

Hom.:

Bravo

AF:

0.00542

Asia WGS

AF:

0.00260

AC:

AN:

3476

EpiCase

AF:

0.00960

EpiControl

AF:

0.0104

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Atypical hemolytic-uremic syndrome with MCP/CD46 anomaly

Benign:3

Jun 28, 2017

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Jul 22, 2015

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:3

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

CD46: BP4, BP7, BS2 -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:2

Jul 08, 2021

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

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Kidney disorder

Benign:1

Nov 10, 2020

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.86

CADD

Benign

0.35

(source)

DANN

Benign

0.64

PhyloP100

-2.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over