1-207767057-T-C

Position:

chr1-207767057-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The ENST00000367042.6(CD46):c.718T>C(p.Ser240Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000434 in 1,613,692 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

CD46
ENST00000367042.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1O:1

Conservation

PhyloP100: -0.788

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 Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CD46	NM_172351.3 linkuse as main transcript	c.718T>C	p.Ser240Pro	missense_variant	6/13	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.718T>C	p.Ser240Pro	missense_variant	6/13	1	NM_172351.3	ENSP00000356009	A2	P15529-11
MIR29B2CHG	ENST00000710901.1 linkuse as main transcript	n.663-4069A>G		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152138

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251270

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135810

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:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000411

AC:

AN:

1461554

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727064

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000450

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152138

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74326

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:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1Other:1

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

Feb 05, 2023

This variant is also known as T822C S206P. This missense change has been observed in individual(s) with hemolytic uremic syndrome (PMID: 14566051). This variant is present in population databases (rs121909589, gnomAD 0.004%). This sequence change replaces serine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 240 of the CD46 protein (p.Ser240Pro). ClinVar contains an entry for this variant (Variation ID: 17046). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt CD46 protein function. Experimental studies have shown that this missense change affects CD46 function (PMID: 14566051). 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 with MCP/CD46 anomaly

Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Oct 28, 2003

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.90

BayesDel_addAF

Uncertain

0.11

BayesDel_noAF

Uncertain

-0.080

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Uncertain

0.43

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

Eigen

Benign

-0.79

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.092

LIST_S2

Benign

0.80

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

M_CAP

Benign

0.063

MetaRNN

Uncertain

0.67

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

MetaSVM

Benign

-0.57

MutationAssessor

Uncertain

2.3

M;M;M;M;M;M;M;.;M;M

MutationTaster

Benign

1.0

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

PrimateAI

Benign

0.32

PROVEAN

Uncertain

-4.0

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

REVEL

Uncertain

0.34

Sift

Uncertain

0.0020

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

Sift4G

Uncertain

0.013

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

Polyphen

0.95

P;D;D;D;D;D;D;.;D;P

Vest4

0.46

MutPred

0.75

Loss of glycosylation at S240 (P = 0.0615);Loss of glycosylation at S240 (P = 0.0615);Loss of glycosylation at S240 (P = 0.0615);Loss of glycosylation at S240 (P = 0.0615);Loss of glycosylation at S240 (P = 0.0615);Loss of glycosylation at S240 (P = 0.0615);Loss of glycosylation at S240 (P = 0.0615);.;Loss of glycosylation at S240 (P = 0.0615);Loss of glycosylation at S240 (P = 0.0615);

MVP

0.68

MPC

0.71

ClinPred

0.85

GERP RS

-4.0

Varity_R

0.72

gMVP

0.87

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