NM_001250.6:c.497+1378T>C

Variant names:

• chr20-46124597-T-C
• rs73115010
• NM_001250.6:c.497+1378T>C

Variant summary

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

The NM_001250.6(CD40):​c.497+1378T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.183 in 151,458 control chromosomes in the GnomAD database, including 3,023 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 0.18 (3023 hom., cov: 29)
• Consequence: CD40 NM_001250.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.40
• Publications: 7 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=-0.91).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.284 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CD40	NM_001250.6	c.497+1378T>C		intron_variant	Intron 5 of 8	ENST00000372285.8	NP_001241.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CD40	ENST00000372285.8	c.497+1378T>C		intron_variant	Intron 5 of 8	1	NM_001250.6	ENSP00000361359.3

Frequencies

GnomAD3 genomes AF: 0.183 AC: 27752 AN: 151346 Hom.: 3021 Cov.: 29

Gnomad AFR AF: 0.0620

Gnomad AMI AF: 0.355

Gnomad AMR AF: 0.157

Gnomad ASJ AF: 0.250

Gnomad EAS AF: 0.296

Gnomad SAS AF: 0.265

Gnomad FIN AF: 0.241

Gnomad MID AF: 0.244

Gnomad NFE AF: 0.234

Gnomad OTH AF: 0.182

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

GnomAD4 genome AF: 0.183 AC: 27758 AN: 151458 Hom.: 3023 Cov.: 29 AF XY: 0.185 AC XY: 13694 AN XY: 73980

African (AFR) AF: 0.0622 AC: 2572 AN: 41348

American (AMR) AF: 0.157 AC: 2391 AN: 15220

Ashkenazi Jewish (ASJ) AF: 0.250 AC: 868 AN: 3466

East Asian (EAS) AF: 0.296 AC: 1525 AN: 5146

South Asian (SAS) AF: 0.266 AC: 1274 AN: 4786

European-Finnish (FIN) AF: 0.241 AC: 2489 AN: 10336

Middle Eastern (MID) AF: 0.238 AC: 69 AN: 290

European-Non Finnish (NFE) AF: 0.234 AC: 15866 AN: 67856

Other (OTH) AF: 0.181 AC: 380 AN: 2098

Alfa AF: 0.206 Hom.: 445

Bravo AF: 0.172

Asia WGS AF: 0.232 AC: 808 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.85
DANN	Benign	0.70
PhyloP100		-1.4
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs73115010; hg19: chr20-44753236;