Genetic Variant NM_172351.3:c.491C>G (chr1-207761264-C-G) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1PM2

The NM_172351.3(CD46):c.491C>G(p.Pro164Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000658 in 151,992 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P164Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Consequence

CD46
NM_172351.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.47

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_172351.3

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CD46	NM_172351.3 link	c.491C>G	p.Pro164Arg	missense_variant	Exon 5 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.491C>G	p.Pro164Arg	missense_variant	Exon 5 of 13	1	NM_172351.3	ENSP00000356009.1		P15529-11

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

151992

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:

0.00

Gnomad OTH

AF:

0.000480

GnomAD3 exomes

AF:

0.00000400

AC:

AN:

250070

Hom.:

AF XY:

0.00000739

AC XY:

AN XY:

135232

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:

0.00

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00000658

AC:

AN:

151992

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74224

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:

0.00

Gnomad4 OTH

AF:

0.000480

ExAC

AF:

0.00000824

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.24

BayesDel_addAF

Benign

-0.059

BayesDel_noAF

Benign

-0.32

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.47

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

Eigen

Uncertain

0.31

Eigen_PC

Benign

0.21

FATHMM_MKL

Uncertain

0.83

LIST_S2

Uncertain

0.88

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

M_CAP

Uncertain

0.12

MetaRNN

Uncertain

0.55

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

MetaSVM

Benign

-0.30

MutationAssessor

Uncertain

2.4

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

PrimateAI

Benign

0.38

PROVEAN

Pathogenic

-6.2

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

REVEL

Benign

0.24

Sift

Benign

0.037

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

Sift4G

Uncertain

0.0020

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

Polyphen

1.0

D;D;D;D;D;D;D;.;D;D

Vest4

0.42

MutPred

0.57

Loss of glycosylation at P164 (P = 0.0238);Loss of glycosylation at P164 (P = 0.0238);Loss of glycosylation at P164 (P = 0.0238);Loss of glycosylation at P164 (P = 0.0238);Loss of glycosylation at P164 (P = 0.0238);Loss of glycosylation at P164 (P = 0.0238);Loss of glycosylation at P164 (P = 0.0238);.;Loss of glycosylation at P164 (P = 0.0238);Loss of glycosylation at P164 (P = 0.0238);

MVP

0.78

MPC

0.53

ClinPred

0.94

GERP RS

2.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.56

gMVP

0.67

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over