NM_172351.3:c.38C>T

Variant names:

• chr1-207752250-C-T
• rs138843816
• NM_172351.3:c.38C>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.38C>T​(p.Ser13Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00207 in 1,614,152 control chromosomes in the GnomAD database, including 59 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0031 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0020 (55 hom.)
• Consequence: CD46 NM_172351.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.449
• Publications: 14 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: Laboratory for Molecular Medicine, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• atypical hemolytic-uremic syndrome

  Inheritance: SD Classification: DEFINITIVE Submitted by: ClinGen

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.003166467).
• BP6: Variant 1-207752250-C-T is Benign according to our data. Variant chr1-207752250-C-T is described in ClinVar as Benign. ClinVar VariationId is 875708.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00305 (465/152372) while in subpopulation EAS AF = 0.0359 (186/5180). AF 95% confidence interval is 0.0317. There are 4 homozygotes in GnomAd4. There are 248 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 AD,AR,SD 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.38C>T	p.Ser13Phe	missense	Exon 1 of 13	NP_758861.1	P15529-11
	CD46	NM_172359.3		c.38C>T	p.Ser13Phe	missense	Exon 1 of 13	NP_758869.1	P15529-2
	CD46	NM_002389.4		c.38C>T	p.Ser13Phe	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.38C>T	p.Ser13Phe	missense	Exon 1 of 13	ENSP00000356009.1	P15529-11
	CD46	ENST00000322875.8	TSL:1	c.38C>T	p.Ser13Phe	missense	Exon 1 of 13	ENSP00000313875.4	P15529-2
	CD46	ENST00000358170.6	TSL:1	c.38C>T	p.Ser13Phe	missense	Exon 1 of 14	ENSP00000350893.2	P15529-1

Frequencies

GnomAD3 genomes AF: 0.00303 AC: 462 AN: 152254 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00383

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00425

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0356

Gnomad SAS AF: 0.00538

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00510 AC: 1282 AN: 251418 AF XY: 0.00418

Gnomad AFR exome AF: 0.00369

Gnomad AMR exome AF: 0.0148

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0321

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000237

Gnomad OTH exome AF: 0.00195

GnomAD4 exome AF: 0.00197 AC: 2883 AN: 1461780 Hom.: 55 Cov.: 31 AF XY: 0.00188 AC XY: 1366 AN XY: 727210

African (AFR) AF: 0.00341 AC: 114 AN: 33478

American (AMR) AF: 0.0138 AC: 619 AN: 44724

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

East Asian (EAS) AF: 0.0384 AC: 1524 AN: 39698

South Asian (SAS) AF: 0.00248 AC: 214 AN: 86258

European-Finnish (FIN) AF: 0.0000562 AC: 3 AN: 53352

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.000232 AC: 258 AN: 1111980

Other (OTH) AF: 0.00247 AC: 149 AN: 60392

GnomAD4 genome AF: 0.00305 AC: 465 AN: 152372 Hom.: 4 Cov.: 32 AF XY: 0.00333 AC XY: 248 AN XY: 74506

African (AFR) AF: 0.00385 AC: 160 AN: 41596

American (AMR) AF: 0.00431 AC: 66 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.0359 AC: 186 AN: 5180

South Asian (SAS) AF: 0.00539 AC: 26 AN: 4828

European-Finnish (FIN) AF: 0.000282 AC: 3 AN: 10626

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

European-Non Finnish (NFE) AF: 0.000265 AC: 18 AN: 68042

Other (OTH) AF: 0.00284 AC: 6 AN: 2116

Alfa AF: 0.00155 Hom.: 2

Bravo AF: 0.00405

ESP6500AA AF: 0.00409 AC: 18

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00500 AC: 607

Asia WGS AF: 0.0170 AC: 60 AN: 3478

EpiCase AF: 0.000327

EpiControl AF: 0.000237

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Atypical hemolytic-uremic syndrome (2)
-	-	2	not provided (2)
-	-	1	Atypical hemolytic-uremic syndrome with MCP/CD46 anomaly (1)
-	-	1	CD46-related disorder (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	2.6
DANN	Benign	0.77
DEOGEN2	Benign	0.17	T
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.96
FATHMM_MKL	Benign	0.18	N
LIST_S2	Uncertain	0.87	D
MetaRNN	Benign	0.0032	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	L
PhyloP100		-0.45
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.094
Sift	Benign	0.14	T
Sift4G	Benign	0.18	T
Polyphen		1.0	D
Vest4		0.065
MVP		0.46
MPC		0.23
ClinPred		0.0050	T
GERP RS		-0.72
PromoterAI		-0.13	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.2
Varity_R		0.044
gMVP		0.54
Mutation Taster		=98/2	polymorphism

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

Other links and lift over

dbSNP: rs138843816; hg19: chr1-207925595; COSMIC: COSV59736141;