chr20-46126219-A-G

Position:

• chr20-46126219-A-G

Variant summary

Our verdict is Benign. Variant got -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

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=-0.87).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.374 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CD40	NM_001250.6	c.498-421A>G		intron_variant		ENST00000372285.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CD40	ENST00000372285.8	c.498-421A>G		intron_variant		1	NM_001250.6	P1

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

Gnomad4 AFR AF: 0.0830

Gnomad4 AMR AF: 0.185

Gnomad4 ASJ AF: 0.190

Gnomad4 EAS AF: 0.385

Gnomad4 SAS AF: 0.393

Gnomad4 FIN AF: 0.284

Gnomad4 NFE AF: 0.210

Gnomad4 OTH AF: 0.194

Alfa AF: 0.0829 Hom.: 148

Bravo AF: 0.109

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

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

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: rs6074028; hg19: chr20-44754858;