1-207752270-C-T

Variant names:

• chr1-207752270-C-T
• NM_172351.3:c.58C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_172351.3(CD46):​c.58C>T​(p.Leu20Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,798 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 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. L20P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CD46 NM_172351.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.900
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• atypical hemolytic-uremic syndrome with MCP/CD46 anomaly

  Inheritance: AD, AR, SD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.054079324).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CD46	NM_172351.3	c.58C>T	p.Leu20Phe	missense_variant	Exon 1 of 13	ENST00000367042.6	NP_758861.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CD46	ENST00000367042.6	c.58C>T	p.Leu20Phe	missense_variant	Exon 1 of 13	1	NM_172351.3	ENSP00000356009.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461798 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727218

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53378

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111974

Other (OTH) AF: 0.00 AC: 0 AN: 60392

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 23, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.58C>T (p.L20F) alteration is located in exon 1 (coding exon 1) of the CD46 gene. This alteration results from a C to T substitution at nucleotide position 58, causing the leucine (L) at amino acid position 20 to be replaced by a phenylalanine (F). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	1.5
DANN	Benign	0.89
DEOGEN2	Benign	0.26	T;.;.;.;.;.;.;.;.;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.072	N
LIST_S2	Benign	0.64	T;T;T;T;T;T;T;T;T;T
M_CAP	Benign	0.031	D
MetaRNN	Benign	0.054	T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.2	L;L;L;L;L;L;L;L;L;L
PhyloP100		-0.90
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-2.0	N;N;N;N;N;N;N;N;N;N
REVEL	Benign	0.018
Sift	Benign	0.042	D;D;T;T;T;T;D;T;T;T
Sift4G	Benign	0.17	T;T;T;T;T;T;T;T;T;T
Polyphen		0.067	B;B;B;B;B;B;B;.;B;B
Vest4		0.084
MutPred		0.33		Loss of disorder (P = 0.2603);Loss of disorder (P = 0.2603);Loss of disorder (P = 0.2603);Loss of disorder (P = 0.2603);Loss of disorder (P = 0.2603);Loss of disorder (P = 0.2603);Loss of disorder (P = 0.2603);Loss of disorder (P = 0.2603);Loss of disorder (P = 0.2603);Loss of disorder (P = 0.2603);
MVP		0.11
MPC		0.21
ClinPred		0.13	T
GERP RS		-0.18
PromoterAI		-0.023	Neutral
Varity_R		0.087
gMVP		0.49
Mutation Taster		=98/2	polymorphism

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

Other links and lift over

hg19: chr1-207925615;