20-46126219-A-G

Variant names:

• chr20-46126219-A-G
• rs6074028
• NM_001250.6:c.498-421A>G

Variant summary

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

The NM_001250.6(CD40):​c.498-421A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. 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 0.20 (1156 hom., cov: 18)
• Consequence: CD40 NM_001250.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.725
• Publications: 6 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.374 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.498-421A>G		intron	N/A	NP_001241.1	P25942-1
	CD40	NM_001322421.2		c.498-421A>G		intron	N/A	NP_001309350.1
	CD40	NM_001302753.2		c.498-421A>G		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.498-421A>G		intron	N/A	ENSP00000361359.3	P25942-1
	CD40	ENST00000372276.7	TSL:1	c.498-1919A>G		intron	N/A	ENSP00000361350.3	P25942-2
	CD40	ENST00000466205.5	TSL:1	n.398-421A>G		intron	N/A	ENSP00000434825.1	H0YE23

Frequencies

GnomAD3 genomes AF: 0.197 AC: 16682 AN: 84780 Hom.: 1153 Cov.: 18

Gnomad AFR AF: 0.0828

Gnomad AMI AF: 0.363

Gnomad AMR AF: 0.185

Gnomad ASJ AF: 0.190

Gnomad EAS AF: 0.385

Gnomad SAS AF: 0.393

Gnomad FIN AF: 0.284

Gnomad MID AF: 0.299

Gnomad NFE AF: 0.210

Gnomad OTH AF: 0.195

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

GnomAD4 genome AF: 0.197 AC: 16689 AN: 84850 Hom.: 1156 Cov.: 18 AF XY: 0.203 AC XY: 8273 AN XY: 40680

African (AFR) AF: 0.0830 AC: 1646 AN: 19830

American (AMR) AF: 0.185 AC: 1411 AN: 7622

Ashkenazi Jewish (ASJ) AF: 0.190 AC: 400 AN: 2100

East Asian (EAS) AF: 0.385 AC: 1345 AN: 3498

South Asian (SAS) AF: 0.393 AC: 1144 AN: 2910

European-Finnish (FIN) AF: 0.284 AC: 1498 AN: 5272

Middle Eastern (MID) AF: 0.306 AC: 55 AN: 180

European-Non Finnish (NFE) AF: 0.210 AC: 8753 AN: 41696

Other (OTH) AF: 0.194 AC: 225 AN: 1158

Alfa AF: 0.0829 Hom.: 148

Bravo AF: 0.109

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.15
DANN	Benign	0.42
PhyloP100		-0.72
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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs6074028;

hg19: chr20-44754858;