rs41258244

Variant names:

• chr1-207761208-A-T
• rs41258244
• NM_172351.3:c.476-41A>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_172351.3(CD46):​c.476-41A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0606 in 1,319,276 control chromosomes in the GnomAD database, including 2,816 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.044 (199 hom., cov: 32)
  • Exomes 𝑓: 0.063 (2617 hom.)
• Consequence: CD46 NM_172351.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.169
• Publications: 4 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: This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 1 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant 1-207761208-A-T is Benign according to our data. Variant chr1-207761208-A-T is described in ClinVar as Benign. ClinVar VariationId is 1271165.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0675 is higher than 0.05.

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.476-41A>T		intron	N/A	NP_758861.1	P15529-11
	CD46	NM_172359.3		c.476-41A>T		intron	N/A	NP_758869.1	P15529-2
	CD46	NM_002389.4		c.476-41A>T		intron	N/A	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.476-41A>T		intron	N/A	ENSP00000356009.1	P15529-11
	CD46	ENST00000322875.8	TSL:1	c.476-41A>T		intron	N/A	ENSP00000313875.4	P15529-2
	CD46	ENST00000358170.6	TSL:1	c.476-41A>T		intron	N/A	ENSP00000350893.2	P15529-1

Frequencies

GnomAD3 genomes AF: 0.0437 AC: 6652 AN: 152210 Hom.: 198 Cov.: 32

Gnomad AFR AF: 0.0112

Gnomad AMI AF: 0.0175

Gnomad AMR AF: 0.0347

Gnomad ASJ AF: 0.0236

Gnomad EAS AF: 0.00615

Gnomad SAS AF: 0.0463

Gnomad FIN AF: 0.0479

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0691

Gnomad OTH AF: 0.0406

GnomAD2 exomes AF: 0.0455 AC: 9165 AN: 201428 AF XY: 0.0468

Gnomad AFR exome AF: 0.0116

Gnomad AMR exome AF: 0.0282

Gnomad ASJ exome AF: 0.0270

Gnomad EAS exome AF: 0.00485

Gnomad FIN exome AF: 0.0464

Gnomad NFE exome AF: 0.0651

Gnomad OTH exome AF: 0.0452

GnomAD4 exome AF: 0.0628 AC: 73306 AN: 1166948 Hom.: 2617 Cov.: 16 AF XY: 0.0619 AC XY: 36585 AN XY: 591378

African (AFR) AF: 0.00949 AC: 260 AN: 27410

American (AMR) AF: 0.0292 AC: 1159 AN: 39652

Ashkenazi Jewish (ASJ) AF: 0.0262 AC: 628 AN: 23984

East Asian (EAS) AF: 0.00451 AC: 169 AN: 37464

South Asian (SAS) AF: 0.0472 AC: 3640 AN: 77134

European-Finnish (FIN) AF: 0.0532 AC: 2704 AN: 50854

Middle Eastern (MID) AF: 0.0206 AC: 88 AN: 4278

European-Non Finnish (NFE) AF: 0.0725 AC: 62070 AN: 855958

Other (OTH) AF: 0.0515 AC: 2588 AN: 50214

GnomAD4 genome AF: 0.0437 AC: 6652 AN: 152328 Hom.: 199 Cov.: 32 AF XY: 0.0419 AC XY: 3120 AN XY: 74494

African (AFR) AF: 0.0111 AC: 463 AN: 41576

American (AMR) AF: 0.0347 AC: 531 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0236 AC: 82 AN: 3470

East Asian (EAS) AF: 0.00617 AC: 32 AN: 5188

South Asian (SAS) AF: 0.0466 AC: 225 AN: 4832

European-Finnish (FIN) AF: 0.0479 AC: 509 AN: 10616

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.0691 AC: 4702 AN: 68020

Other (OTH) AF: 0.0397 AC: 84 AN: 2114

Alfa AF: 0.0510 Hom.: 42

Bravo AF: 0.0398

Asia WGS AF: 0.0240 AC: 84 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	8.0
DANN	Benign	0.90
PhyloP100		0.17
BranchPoint Hunter		1.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs41258244; hg19: chr1-207934553;