1-207752271-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_172351.3(CD46):c.59T>C(p.Leu20Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 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. L20F) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CD46 NM_172351.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.162

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.23984644).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CD46	NM_172351.3	c.59T>C	p.Leu20Pro	missense_variant	1/13	ENST00000367042.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CD46	ENST00000367042.6	c.59T>C	p.Leu20Pro	missense_variant	1/13	1	NM_172351.3	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Sep 01, 2022

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. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0". The proline amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. This variant has not been reported in the literature in individuals affected with CD46-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 20 of the CD46 protein (p.Leu20Pro). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.087	T
BayesDel_noAF	Benign	-0.36
Cadd	Benign	18
Dann	Uncertain	0.98
DEOGEN2	Uncertain	0.53	D;.;.;.;.;.;.;.;.;.
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.83
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.58	T;T;T;T;T;T;T;T;T;T
M_CAP	Benign	0.040	D
MetaRNN	Benign	0.24	T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	1.9	L;L;L;L;L;L;L;L;L;L
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N;N;N;N;N
PrimateAI	Benign	0.35	T
PROVEAN	Uncertain	-4.3	D;D;D;D;D;D;D;N;D;D
REVEL	Benign	0.15
Sift	Uncertain	0.0010	D;D;D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.018	D;D;D;D;D;D;D;D;D;D
Polyphen		1.0	D;D;D;D;D;D;D;.;D;D
Vest4		0.24
MutPred		0.66		Gain of disorder (P = 0.0107);Gain of disorder (P = 0.0107);Gain of disorder (P = 0.0107);Gain of disorder (P = 0.0107);Gain of disorder (P = 0.0107);Gain of disorder (P = 0.0107);Gain of disorder (P = 0.0107);Gain of disorder (P = 0.0107);Gain of disorder (P = 0.0107);Gain of disorder (P = 0.0107);
MVP		0.40
MPC		0.80
ClinPred		0.90	D
GERP RS		-0.52
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.51
gMVP		0.75

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

LitVar

Other links and lift over

dbSNP: rs1238861656; hg19: chr1-207925616;