rs11569309

chr20-46119911-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001250.6(CD40):c.51+1517T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.138 in 152,098 control chromosomes in the GnomAD database, including 1,714 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 0.14 (1714 hom., cov: 32)
• Consequence: CD40 NM_001250.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.29

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.188 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CD40	NM_001250.6	c.51+1517T>C		intron_variant		ENST00000372285.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CD40	ENST00000372285.8	c.51+1517T>C		intron_variant		1	NM_001250.6	P1

Frequencies

GnomAD3 genomes AF: 0.138 AC: 20937 AN: 151980 Hom.: 1713 Cov.: 32

Gnomad AFR AF: 0.0558

Gnomad AMI AF: 0.163

Gnomad AMR AF: 0.101

Gnomad ASJ AF: 0.160

Gnomad EAS AF: 0.0310

Gnomad SAS AF: 0.112

Gnomad FIN AF: 0.223

Gnomad MID AF: 0.133

Gnomad NFE AF: 0.191

Gnomad OTH AF: 0.145

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

GnomAD4 genome AF: 0.138 AC: 20934 AN: 152098 Hom.: 1714 Cov.: 32 AF XY: 0.136 AC XY: 10136 AN XY: 74338

Gnomad4 AFR AF: 0.0557

Gnomad4 AMR AF: 0.101

Gnomad4 ASJ AF: 0.160

Gnomad4 EAS AF: 0.0311

Gnomad4 SAS AF: 0.112

Gnomad4 FIN AF: 0.223

Gnomad4 NFE AF: 0.191

Gnomad4 OTH AF: 0.143

Alfa AF: 0.171 Hom.: 453

Bravo AF: 0.126

Asia WGS AF: 0.0810 AC: 281 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
Cadd	Benign	1.9
Dann	Benign	0.48

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

Publications

LitVar

Other links and lift over

dbSNP: rs11569309; hg19: chr20-44748550;