rs12126088

Positions:

• chr1-207759666-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_172351.3(CD46):​c.417A>G​(p.Leu139=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00718 in 1,595,512 control chromosomes in the GnomAD database, including 51 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0057 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0073 (48 hom.)
• Consequence: CD46 NM_172351.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -2.17

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 Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 1-207759666-A-G is Benign according to our data. Variant chr1-207759666-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 522216.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-207759666-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-2.17 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00574 (875/152346) while in subpopulation NFE AF= 0.00853 (580/68030). AF 95% confidence interval is 0.00795. There are 3 homozygotes in gnomad4. There are 429 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 3 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CD46	NM_172351.3	c.417A>G	p.Leu139=	synonymous_variant	4/13	ENST00000367042.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CD46	ENST00000367042.6	c.417A>G	p.Leu139=	synonymous_variant	4/13	1	NM_172351.3	A2

Frequencies

GnomAD3 genomes AF: 0.00575 AC: 875 AN: 152228 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.00121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00543

Gnomad ASJ AF: 0.0225

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00612

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00852

Gnomad OTH AF: 0.00334

GnomAD3 exomes AF: 0.00666 AC: 1663 AN: 249636 Hom.: 9 AF XY: 0.00679 AC XY: 917 AN XY: 135082

Gnomad AFR exome AF: 0.00107

Gnomad AMR exome AF: 0.00395

Gnomad ASJ exome AF: 0.0184

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.00201

Gnomad FIN exome AF: 0.00574

Gnomad NFE exome AF: 0.00960

Gnomad OTH exome AF: 0.00905

GnomAD4 exome AF: 0.00733 AC: 10576 AN: 1443166 Hom.: 48 Cov.: 26 AF XY: 0.00725 AC XY: 5210 AN XY: 719014

Gnomad4 AFR exome AF: 0.000785

Gnomad4 AMR exome AF: 0.00401

Gnomad4 ASJ exome AF: 0.0176

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.00199

Gnomad4 FIN exome AF: 0.00658

Gnomad4 NFE exome AF: 0.00816

Gnomad4 OTH exome AF: 0.00689

GnomAD4 genome AF: 0.00574 AC: 875 AN: 152346 Hom.: 3 Cov.: 33 AF XY: 0.00576 AC XY: 429 AN XY: 74500

Gnomad4 AFR AF: 0.00120

Gnomad4 AMR AF: 0.00542

Gnomad4 ASJ AF: 0.0225

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00166

Gnomad4 FIN AF: 0.00612

Gnomad4 NFE AF: 0.00853

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00862 Hom.: 3

Bravo AF: 0.00542

Asia WGS AF: 0.00260 AC: 9 AN: 3476

EpiCase AF: 0.00960

EpiControl AF: 0.0104

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Atypical hemolytic-uremic syndrome with MCP/CD46 anomaly Benign:3

Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Jun 28, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Jul 22, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	CD46: BP4, BP7, BS2 -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 08, 2021	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Kidney disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Nov 10, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.35
DANN	Benign	0.64
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs12126088; hg19: chr1-207933011;