chr1-207752229-G-T

Variant names:

• chr1-207752229-G-T
• rs749796669
• NM_172351.3:c.17G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_172351.3(CD46):​c.17G>T​(p.Arg6Leu) 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 1,461,592 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar 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: 0.466
• 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, SD, AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Laboratory for Molecular Medicine
• atypical hemolytic-uremic syndrome

  Inheritance: SD Classification: DEFINITIVE Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20220205).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_172351.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CD46	NM_172351.3	MANE Select	c.17G>T	p.Arg6Leu	missense	Exon 1 of 13	NP_758861.1	P15529-11
	CD46	NM_172359.3		c.17G>T	p.Arg6Leu	missense	Exon 1 of 13	NP_758869.1	P15529-2
	CD46	NM_002389.4		c.17G>T	p.Arg6Leu	missense	Exon 1 of 14	NP_002380.3	P15529-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CD46	ENST00000367042.6	TSL:1 MANE Select	c.17G>T	p.Arg6Leu	missense	Exon 1 of 13	ENSP00000356009.1	P15529-11
	CD46	ENST00000322875.8	TSL:1	c.17G>T	p.Arg6Leu	missense	Exon 1 of 13	ENSP00000313875.4	P15529-2
	CD46	ENST00000358170.6	TSL:1	c.17G>T	p.Arg6Leu	missense	Exon 1 of 14	ENSP00000350893.2	P15529-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251292 AF XY: 0.00000736

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461592 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727140

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53188

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111966

Other (OTH) AF: 0.00 AC: 0 AN: 60388

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.28	T
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.75
FATHMM_MKL	Benign	0.59	D
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.045	D
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		0.47
PrimateAI	Benign	0.34	T
PROVEAN	Uncertain	-2.9	D
REVEL	Benign	0.086
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.028	D
Polyphen		0.99	D
Vest4		0.22
MutPred		0.36		Loss of disorder (P = 0.0456)
MVP		0.47
MPC		0.72
ClinPred		0.86	D
GERP RS		0.23
PromoterAI		0.079	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.2
Varity_R		0.25
gMVP		0.49
Mutation Taster		=94/6	polymorphism

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

Other links and lift over

dbSNP: rs749796669; hg19: chr1-207925574;