20-46119308-T-G

Variant names:

• chr20-46119308-T-G
• rs4810485
• NM_001250.6:c.51+914T>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001322421.2(CD40):​c.51+914T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.786 in 152,190 control chromosomes in the GnomAD database, including 47,588 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.79 (47588 hom., cov: 33)
• Consequence: CD40 NM_001322421.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.447
• Publications: 245 publications found

Genes affected

CD40 (HGNC:11919): (CD40 molecule) This gene is a member of the TNF-receptor superfamily. The encoded protein is a receptor on antigen-presenting cells of the immune system and is essential for mediating a broad variety of immune and inflammatory responses including T cell-dependent immunoglobulin class switching, memory B cell development, and germinal center formation. AT-hook transcription factor AKNA is reported to coordinately regulate the expression of this receptor and its ligand, which may be important for homotypic cell interactions. Adaptor protein TNFR2 interacts with this receptor and serves as a mediator of the signal transduction. The interaction of this receptor and its ligand is found to be necessary for amyloid-beta-induced microglial activation, and thus is thought to be an early event in Alzheimer disease pathogenesis. Mutations affecting this gene are the cause of autosomal recessive hyper-IgM immunodeficiency type 3 (HIGM3). Multiple alternatively spliced transcript variants of this gene encoding distinct isoforms have been reported. [provided by RefSeq, Nov 2014]

CD40 Gene-Disease associations (from GenCC):

• hyper-IgM syndrome type 3

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.91 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001322421.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CD40	NM_001250.6	MANE Select	c.51+914T>G		intron	N/A	NP_001241.1
	CD40	NM_001322421.2		c.51+914T>G		intron	N/A	NP_001309350.1
	CD40	NM_001302753.2		c.51+914T>G		intron	N/A	NP_001289682.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CD40	ENST00000372285.8	TSL:1 MANE Select	c.51+914T>G		intron	N/A	ENSP00000361359.3
	CD40	ENST00000372276.7	TSL:1	c.51+914T>G		intron	N/A	ENSP00000361350.3
	CD40	ENST00000466205.5	TSL:1	n.45+914T>G		intron	N/A	ENSP00000434825.1

Frequencies

GnomAD3 genomes AF: 0.785 AC: 119431 AN: 152072 Hom.: 47532 Cov.: 33

Gnomad AFR AF: 0.918

Gnomad AMI AF: 0.759

Gnomad AMR AF: 0.771

Gnomad ASJ AF: 0.727

Gnomad EAS AF: 0.563

Gnomad SAS AF: 0.735

Gnomad FIN AF: 0.723

Gnomad MID AF: 0.725

Gnomad NFE AF: 0.742

Gnomad OTH AF: 0.760

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.786 AC: 119547 AN: 152190 Hom.: 47588 Cov.: 33 AF XY: 0.780 AC XY: 58003 AN XY: 74388

African (AFR) AF: 0.918 AC: 38129 AN: 41546

American (AMR) AF: 0.771 AC: 11803 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.727 AC: 2525 AN: 3472

East Asian (EAS) AF: 0.563 AC: 2911 AN: 5170

South Asian (SAS) AF: 0.735 AC: 3535 AN: 4812

European-Finnish (FIN) AF: 0.723 AC: 7655 AN: 10586

Middle Eastern (MID) AF: 0.724 AC: 213 AN: 294

European-Non Finnish (NFE) AF: 0.742 AC: 50472 AN: 67982

Other (OTH) AF: 0.763 AC: 1612 AN: 2114

Alfa AF: 0.754 Hom.: 162072

Bravo AF: 0.796

Asia WGS AF: 0.723 AC: 2517 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	1.1
DANN	Benign	0.46
PhyloP100		-0.45
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs4810485; hg19: chr20-44747947;