20-46119460-C-T

Variant names:

• chr20-46119460-C-T
• rs1535045
• NM_001250.6:c.51+1066C>T

Variant summary

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

The NM_001250.6(CD40):​c.51+1066C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.191 in 151,812 control chromosomes in the GnomAD database, including 3,324 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 0.19 (3324 hom., cov: 31)
• Consequence: CD40 NM_001250.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.640
• Publications: 35 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: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae)

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.301 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001250.6. 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
	CD40	NM_001250.6	MANE Select	c.51+1066C>T		intron	N/A	NP_001241.1	P25942-1
	CD40	NM_001322421.2		c.51+1066C>T		intron	N/A	NP_001309350.1
	CD40	NM_001302753.2		c.51+1066C>T		intron	N/A	NP_001289682.1	A0A8Q3SI60

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CD40	ENST00000372285.8	TSL:1 MANE Select	c.51+1066C>T		intron	N/A	ENSP00000361359.3	P25942-1
	CD40	ENST00000372276.7	TSL:1	c.51+1066C>T		intron	N/A	ENSP00000361350.3	P25942-2
	CD40	ENST00000466205.5	TSL:1	n.45+1066C>T		intron	N/A	ENSP00000434825.1	H0YE23

Frequencies

GnomAD3 genomes AF: 0.191 AC: 29047 AN: 151692 Hom.: 3320 Cov.: 31

Gnomad AFR AF: 0.0660

Gnomad AMI AF: 0.356

Gnomad AMR AF: 0.162

Gnomad ASJ AF: 0.296

Gnomad EAS AF: 0.282

Gnomad SAS AF: 0.314

Gnomad FIN AF: 0.248

Gnomad MID AF: 0.264

Gnomad NFE AF: 0.242

Gnomad OTH AF: 0.192

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

GnomAD4 genome AF: 0.191 AC: 29058 AN: 151812 Hom.: 3324 Cov.: 31 AF XY: 0.193 AC XY: 14348 AN XY: 74194

African (AFR) AF: 0.0660 AC: 2733 AN: 41384

American (AMR) AF: 0.162 AC: 2469 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.296 AC: 1027 AN: 3466

East Asian (EAS) AF: 0.282 AC: 1454 AN: 5150

South Asian (SAS) AF: 0.315 AC: 1507 AN: 4790

European-Finnish (FIN) AF: 0.248 AC: 2616 AN: 10546

Middle Eastern (MID) AF: 0.260 AC: 76 AN: 292

European-Non Finnish (NFE) AF: 0.242 AC: 16442 AN: 67904

Other (OTH) AF: 0.195 AC: 410 AN: 2106

Alfa AF: 0.121 Hom.: 225

Bravo AF: 0.179

Asia WGS AF: 0.238 AC: 831 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.62
DANN	Benign	0.74
PhyloP100		-0.64
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: rs1535045; hg19: chr20-44748099;