1-207752282-A-G

Position:

chr1-207752282-A-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_172351.3(CD46):c.70A>G(p.Met24Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000824 in 1,613,888 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M24I) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000088 ( 0 hom. )

Consequence

CD46
NM_172351.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:2

Conservation

PhyloP100: -2.37

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 Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.042957544).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CD46	NM_172351.3 linkuse as main transcript	c.70A>G	p.Met24Val	missense_variant	1/13	ENST00000367042.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CD46	ENST00000367042.6 linkuse as main transcript	c.70A>G	p.Met24Val	missense_variant	1/13	1	NM_172351.3	A2	P15529-11

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152102

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.0000441

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000358

AC:

AN:

251364

Hom.:

AF XY:

0.0000442

AC XY:

AN XY:

135874

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.0000792

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000876

AC:

128

AN:

1461786

Hom.:

Cov.:

AF XY:

0.0000866

AC XY:

AN XY:

727218

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.00

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:

0.000111

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000329

AC:

AN:

152102

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74298

show subpopulations

Gnomad4 AFR

AF:

0.0000241

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:

0.0000441

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.000113

Hom.:

Bravo

AF:

0.0000302

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 28, 2023

This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 24 of the CD46 protein (p.Met24Val). This variant is present in population databases (rs750342865, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with CD46-related conditions. ClinVar contains an entry for this variant (Variation ID: 988105). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The valine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Atypical hemolytic-uremic syndrome

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Sydney Genome Diagnostics, Children's Hospital Westmead

Mar 06, 2018

This patient is heterozygous for a variant of unknown clinical significance (VOUS), c.70A>G p.(Met24Val), in the CD46 gene. To our knowledge, this variant has not been reported as being associated with disease in the literature. However, this variant (dbSNP: rs750342865) has been previously reported in the Exome Aggregation Consortium (ExAC) database (http://exac.broadinstitute.org/) with a very low allele frequency of 0.0025% (3 out of 121,328 alleles). In silico analysis of pathogenicity (through Alamut Visual v2.8.1) using SIFT, Mutation Taster and PolyPhen2 all predict that this variant is likely to be benign. This variant is considered to be a variant of uncertain clinical significance (VOUS) according to the ACMG guidelines. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.069

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.75

CADD

Benign

0.029

DANN

Benign

0.51

DEOGEN2

Benign

0.12

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

Eigen

Benign

-1.9

Eigen_PC

Benign

-2.0

FATHMM_MKL

Benign

0.035

LIST_S2

Benign

0.48

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

M_CAP

Benign

0.0092

MetaRNN

Benign

0.043

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

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.0

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

MutationTaster

Benign

1.0

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

PrimateAI

Benign

0.27

PROVEAN

Benign

-0.81

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

REVEL

Benign

0.012

Sift

Benign

0.057

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

Sift4G

Benign

0.077

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

Polyphen

0.0

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

Vest4

0.039

MutPred

0.51

Loss of phosphorylation at Y29 (P = 0.202);Loss of phosphorylation at Y29 (P = 0.202);Loss of phosphorylation at Y29 (P = 0.202);Loss of phosphorylation at Y29 (P = 0.202);Loss of phosphorylation at Y29 (P = 0.202);Loss of phosphorylation at Y29 (P = 0.202);Loss of phosphorylation at Y29 (P = 0.202);Loss of phosphorylation at Y29 (P = 0.202);Loss of phosphorylation at Y29 (P = 0.202);Loss of phosphorylation at Y29 (P = 0.202);

MVP

0.055

MPC

0.15

ClinPred

0.095

GERP RS

-6.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.15

gMVP

0.43

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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