rs35366573

Variant names:

• chr1-207785101-C-T
• rs35366573
• NM_172351.3:c.1013C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_172351.3(CD46):​c.1013C>T​(p.Ala338Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0172 in 1,610,994 control chromosomes in the GnomAD database, including 392 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A338A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.014 (39 hom., cov: 32)
  • Exomes 𝑓: 0.018 (353 hom.)
• Consequence: CD46 NM_172351.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -4.38
• Publications: 51 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]

MIR29B2CHG (HGNC:32018): (MIR29B2 and MIR29C host gene)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002087295).
• BP6: Variant 1-207785101-C-T is Benign according to our data. Variant chr1-207785101-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 294975.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0142 (2166/152200) while in subpopulation NFE AF = 0.0191 (1298/67998). AF 95% confidence interval is 0.0182. There are 39 homozygotes in GnomAd4. There are 1123 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 39 AD,SD,AR gene

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.1013C>T	p.Ala338Val	missense	Exon 10 of 13	NP_758861.1	P15529-11
	CD46	NM_172359.3		c.1058C>T	p.Ala353Val	missense	Exon 11 of 13	NP_758869.1	P15529-2
	CD46	NM_002389.4		c.1058C>T	p.Ala353Val	missense	Exon 11 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.1013C>T	p.Ala338Val	missense	Exon 10 of 13	ENSP00000356009.1	P15529-11
	CD46	ENST00000322875.8	TSL:1	c.1058C>T	p.Ala353Val	missense	Exon 11 of 13	ENSP00000313875.4	P15529-2
	CD46	ENST00000358170.6	TSL:1	c.1058C>T	p.Ala353Val	missense	Exon 11 of 14	ENSP00000350893.2	P15529-1

Frequencies

GnomAD3 genomes AF: 0.0142 AC: 2166 AN: 152082 Hom.: 39 Cov.: 32

Gnomad AFR AF: 0.00268

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00380

Gnomad ASJ AF: 0.00922

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.0607

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0191

Gnomad OTH AF: 0.00909

GnomAD2 exomes AF: 0.0151 AC: 3782 AN: 250790 AF XY: 0.0151

Gnomad AFR exome AF: 0.00228

Gnomad AMR exome AF: 0.00180

Gnomad ASJ exome AF: 0.00795

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0586

Gnomad NFE exome AF: 0.0196

Gnomad OTH exome AF: 0.0118

GnomAD4 exome AF: 0.0176 AC: 25611 AN: 1458794 Hom.: 353 Cov.: 29 AF XY: 0.0171 AC XY: 12433 AN XY: 725836

African (AFR) AF: 0.00227 AC: 76 AN: 33424

American (AMR) AF: 0.00235 AC: 105 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.00762 AC: 199 AN: 26110

East Asian (EAS) AF: 0.00 AC: 0 AN: 39662

South Asian (SAS) AF: 0.00165 AC: 142 AN: 86146

European-Finnish (FIN) AF: 0.0553 AC: 2950 AN: 53370

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5764

European-Non Finnish (NFE) AF: 0.0193 AC: 21425 AN: 1109338

Other (OTH) AF: 0.0118 AC: 711 AN: 60280

GnomAD4 genome AF: 0.0142 AC: 2166 AN: 152200 Hom.: 39 Cov.: 32 AF XY: 0.0151 AC XY: 1123 AN XY: 74422

African (AFR) AF: 0.00267 AC: 111 AN: 41528

American (AMR) AF: 0.00379 AC: 58 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00922 AC: 32 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4822

European-Finnish (FIN) AF: 0.0607 AC: 643 AN: 10588

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0191 AC: 1298 AN: 67998

Other (OTH) AF: 0.00900 AC: 19 AN: 2112

Alfa AF: 0.0172 Hom.: 112

Bravo AF: 0.0102

TwinsUK AF: 0.0218 AC: 81

ALSPAC AF: 0.0192 AC: 74

ESP6500AA AF: 0.00295 AC: 13

ESP6500EA AF: 0.0173 AC: 149

ExAC AF: 0.0149 AC: 1805

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.0162

EpiControl AF: 0.0169

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	Atypical hemolytic-uremic syndrome (2)
-	-	2	Atypical hemolytic-uremic syndrome with MCP/CD46 anomaly (2)
-	-	2	not provided (2)
-	-	1	Myofibrillar myopathy 6 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	0.034
DANN	Benign	0.52
DEOGEN2	Benign	0.11	T
Eigen	Benign	-2.1
Eigen_PC	Benign	-2.2
FATHMM_MKL	Benign	0.0043	N
LIST_S2	Benign	0.63	T
MetaRNN	Benign	0.0021	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.77	N
PhyloP100		-4.4
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-0.11	N
REVEL	Benign	0.031
Sift	Benign	0.47	T
Sift4G	Benign	0.63	T
Polyphen		0.0010	B
Vest4		0.10
MPC		0.15
ClinPred		0.0067	T
GERP RS		-8.7
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		2.1
Varity_R		0.012
gMVP		0.13
Mutation Taster		=95/5	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
SpliceAI score (max)		0.11		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: rs35366573; hg19: chr1-207958446; COSMIC: COSV59731245;