20-46126219-A-C

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001250.6(CD40):​c.498-421A>C 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 0.039 (0 hom., cov: 18)
  • Failed GnomAD Quality Control
• 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: ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CD40	NM_001250.6	MANE Select	c.498-421A>C		intron	N/A	NP_001241.1
	CD40	NM_001322421.2		c.498-421A>C		intron	N/A	NP_001309350.1
	CD40	NM_001302753.2		c.498-421A>C		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.498-421A>C		intron	N/A	ENSP00000361359.3
	CD40	ENST00000372276.7	TSL:1	c.498-1919A>C		intron	N/A	ENSP00000361350.3
	CD40	ENST00000466205.5	TSL:1	n.398-421A>C		intron	N/A	ENSP00000434825.1

Frequencies

GnomAD3 genomes AF: 0.0388 AC: 3051 AN: 78600 Hom.: 0 Cov.: 18

Gnomad AFR AF: 0.0497

Gnomad AMI AF: 0.0374

Gnomad AMR AF: 0.0295

Gnomad ASJ AF: 0.0345

Gnomad EAS AF: 0.0102

Gnomad SAS AF: 0.0203

Gnomad FIN AF: 0.0217

Gnomad MID AF: 0.00521

Gnomad NFE AF: 0.0420

Gnomad OTH AF: 0.0403

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

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0388 AC: 3051 AN: 78664 Hom.: 0 Cov.: 18 AF XY: 0.0361 AC XY: 1374 AN XY: 38016

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0495 AC: 894 AN: 18068

American (AMR) AF: 0.0295 AC: 212 AN: 7182

Ashkenazi Jewish (ASJ) AF: 0.0345 AC: 66 AN: 1914

East Asian (EAS) AF: 0.0102 AC: 35 AN: 3416

South Asian (SAS) AF: 0.0203 AC: 57 AN: 2808

European-Finnish (FIN) AF: 0.0217 AC: 109 AN: 5032

Middle Eastern (MID) AF: 0.00562 AC: 1 AN: 178

European-Non Finnish (NFE) AF: 0.0420 AC: 1614 AN: 38450

Other (OTH) AF: 0.0398 AC: 42 AN: 1054

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 148

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.14
DANN	Benign	0.57
PhyloP100		-0.72

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: rs6074028; hg19: chr20-44754858;