1-207752250-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_172351.3(CD46):c.38C>T(p.Ser13Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00207 in 1,614,152 control chromosomes in the GnomAD database, including 59 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0031 ( 4 hom., cov: 32)

Exomes 𝑓: 0.0020 ( 55 hom. )

Consequence

CD46
NM_172351.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -0.449

Publications

14 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.003166467).

BP6

Variant 1-207752250-C-T is Benign according to our data. Variant chr1-207752250-C-T is described in ClinVar as [Benign]. Clinvar id is 875708.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00305 (465/152372) while in subpopulation EAS AF = 0.0359 (186/5180). AF 95% confidence interval is 0.0317. There are 4 homozygotes in GnomAd4. There are 248 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 4 AD,AR,SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CD46	NM_172351.3 link	c.38C>T	p.Ser13Phe	missense_variant	Exon 1 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.38C>T	p.Ser13Phe	missense_variant	Exon 1 of 13	1	NM_172351.3	ENSP00000356009.1		P15529-11

Frequencies

GnomAD3 genomes

AF:

0.00303

AC:

462

AN:

152254

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00383

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00425

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0356

Gnomad SAS

AF:

0.00538

Gnomad FIN

AF:

0.000282

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000265

Gnomad OTH

AF:

0.00287

GnomAD2 exomes

AF:

0.00510

AC:

1282

AN:

251418

AF XY:

0.00418

show subpopulations

Gnomad AFR exome

AF:

0.00369

Gnomad AMR exome

AF:

0.0148

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0321

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000237

Gnomad OTH exome

AF:

0.00195

GnomAD4 exome

AF:

0.00197

AC:

2883

AN:

1461780

Hom.:

Cov.:

AF XY:

0.00188

AC XY:

1366

AN XY:

727210

show subpopulations

African (AFR)

AF:

0.00341

AC:

114

AN:

33478

American (AMR)

AF:

0.0138

AC:

619

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26130

East Asian (EAS)

AF:

0.0384

AC:

1524

AN:

39698

South Asian (SAS)

AF:

0.00248

AC:

214

AN:

86258

European-Finnish (FIN)

AF:

0.0000562

AC:

AN:

53352

Middle Eastern (MID)

AF:

0.000347

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000232

AC:

258

AN:

1111980

Other (OTH)

AF:

0.00247

AC:

149

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

213

425

638

850

1063

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00305

AC:

465

AN:

152372

Hom.:

Cov.:

AF XY:

0.00333

AC XY:

248

AN XY:

74506

show subpopulations

African (AFR)

AF:

0.00385

AC:

160

AN:

41596

American (AMR)

AF:

0.00431

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.0359

AC:

186

AN:

5180

South Asian (SAS)

AF:

0.00539

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.000282

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000265

AC:

AN:

68042

Other (OTH)

AF:

0.00284

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

124

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00155

Hom.:

Bravo

AF:

0.00405

ESP6500AA

AF:

0.00409

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00500

AC:

607

Asia WGS

AF:

0.0170

AC:

AN:

3478

EpiCase

AF:

0.000327

EpiControl

AF:

0.000237

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

Sep 02, 2022

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

CD46-related disorder

Benign:1

Oct 31, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Atypical hemolytic-uremic syndrome with MCP/CD46 anomaly

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Atypical hemolytic-uremic syndrome

Benign:1

Feb 25, 2022

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.45

CADD

Benign

2.6

(source)

DANN

Benign

0.77

DEOGEN2

Benign

0.17

T;.;.;.;.;.;.;.;.;.

Eigen

Benign

-0.77

Eigen_PC

Benign

-0.96

FATHMM_MKL

Benign

0.18

LIST_S2

Uncertain

0.87

D;D;T;D;T;T;D;T;T;D

MetaRNN

Benign

0.0032

T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.6

L;L;L;L;L;L;L;L;L;L

PhyloP100

-0.45

PrimateAI

Benign

0.32

PROVEAN

Benign

-1.6

N;N;N;N;N;N;N;N;N;N

REVEL

Benign

0.094

Sift

Benign

0.14

T;T;T;T;T;T;T;D;T;T

Sift4G

Benign

0.18

T;T;T;T;T;T;T;D;T;T

Polyphen

1.0

D;B;B;B;D;B;B;.;B;D

Vest4

0.065

MVP

0.46

MPC

0.23

ClinPred

0.0050

GERP RS

-0.72

PromoterAI

-0.13

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.2

Varity_R

0.044

gMVP

0.54

Mutation Taster

=98/2

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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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1-207752250-C-T

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