1-207785101-C-T

Position:

chr1-207785101-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_172351.3(CD46):c.1013C>T(p.Ala338Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0172 in 1,610,994 control chromosomes in the GnomAD database, including 392 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.014 ( 39 hom., cov: 32)

Exomes 𝑓: 0.018 ( 353 hom. )

Consequence

CD46
NM_172351.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -4.38

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:

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

MIR29B2CHG links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.002087295).

BP6

Variant 1-207785101-C-T is Benign according to our data. Variant chr1-207785101-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 294975.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-207785101-C-T is described in Lovd as [Benign]. Variant chr1-207785101-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0142 (2166/152200) while in subpopulation NFE AF= 0.0191 (1298/67998). AF 95% confidence interval is 0.0182. There are 39 homozygotes in gnomad4. There are 1123 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 39 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CD46	NM_172351.3 linkuse as main transcript	c.1013C>T	p.Ala338Val	missense_variant	10/13	ENST00000367042.6	NP_758861.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CD46	ENST00000367042.6 linkuse as main transcript	c.1013C>T	p.Ala338Val	missense_variant	10/13	1	NM_172351.3	ENSP00000356009	A2	P15529-11
MIR29B2CHG	ENST00000710901.1 linkuse as main transcript	n.662+20904G>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.0142

AC:

2166

AN:

152082

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00268

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00380

Gnomad ASJ

AF:

0.00922

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00104

Gnomad FIN

AF:

0.0607

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0191

Gnomad OTH

AF:

0.00909

GnomAD3 exomes

AF:

0.0151

AC:

3782

AN:

250790

Hom.:

AF XY:

0.0151

AC XY:

2042

AN XY:

135562

show subpopulations

Gnomad AFR exome

AF:

0.00228

Gnomad AMR exome

AF:

0.00180

Gnomad ASJ exome

AF:

0.00795

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00154

Gnomad FIN exome

AF:

0.0586

Gnomad NFE exome

AF:

0.0196

Gnomad OTH exome

AF:

0.0118

GnomAD4 exome

AF:

0.0176

AC:

25611

AN:

1458794

Hom.:

353

Cov.:

AF XY:

0.0171

AC XY:

12433

AN XY:

725836

show subpopulations

Gnomad4 AFR exome

AF:

0.00227

Gnomad4 AMR exome

AF:

0.00235

Gnomad4 ASJ exome

AF:

0.00762

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00165

Gnomad4 FIN exome

AF:

0.0553

Gnomad4 NFE exome

AF:

0.0193

Gnomad4 OTH exome

AF:

0.0118

GnomAD4 genome

AF:

0.0142

AC:

2166

AN:

152200

Hom.:

Cov.:

AF XY:

0.0151

AC XY:

1123

AN XY:

74422

show subpopulations

Gnomad4 AFR

AF:

0.00267

Gnomad4 AMR

AF:

0.00379

Gnomad4 ASJ

AF:

0.00922

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00104

Gnomad4 FIN

AF:

0.0607

Gnomad4 NFE

AF:

0.0191

Gnomad4 OTH

AF:

0.00900

Alfa

AF:

0.0169

Hom.:

Bravo

AF:

0.0102

TwinsUK

AF:

0.0218

AC:

ALSPAC

AF:

0.0192

AC:

ESP6500AA

AF:

0.00295

AC:

ESP6500EA

AF:

0.0173

AC:

149

ExAC

AF:

0.0149

AC:

1805

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.0162

EpiControl

AF:

0.0169

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Atypical hemolytic-uremic syndrome with MCP/CD46 anomaly

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Mendelics	Apr 24, 2024	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	CD46: BP4, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Myofibrillar myopathy 6

Benign:1

Likely benign, criteria provided, single submitter

research

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

The heterozygous p.Ala353Val variant in CD46 has been identified in an individual with haemolytic uraemic syndrome and no known relatives with disease (PMID: 16621965), but has been identified in >6% of European (Finnish) chromosomes by ExAC (http://gnomad.broadinstitute.org/). Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely benign for haemolytic uraemic syndrome. -

Atypical hemolytic-uremic syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Sep 01, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.63

BayesDel_noAF

Benign

-0.66

CADD

Benign

0.034

DANN

Benign

0.52

DEOGEN2

Benign

0.11

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

Eigen

Benign

-2.1

Eigen_PC

Benign

-2.2

FATHMM_MKL

Benign

0.0043

LIST_S2

Benign

0.63

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

MetaRNN

Benign

0.0021

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

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.77

N;.;.;.;.;.;N;.;.;.

MutationTaster

Benign

1.0

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

PrimateAI

Benign

0.23

PROVEAN

Benign

-0.11

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

REVEL

Benign

0.031

Sift

Benign

0.47

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

Sift4G

Benign

0.63

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

Polyphen

0.0010

B;B;B;B;B;B;B;.;B;B

Vest4

0.10

MPC

0.15

ClinPred

0.0067

GERP RS

-8.7

RBP_binding_hub_radar

1.0

RBP_regulation_power_radar

2.1

Varity_R

0.012

gMVP

0.13

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.11

Details are displayed if max score is > 0.2

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