20-46126219-A-C

Position:

• chr20-46126219-A-C

Variant summary

Our verdict is Likely benign. Variant got -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

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 Likely_benign. Variant got -4 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CD40	NM_001250.6	c.498-421A>C		intron_variant		ENST00000372285.8	NP_001241.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CD40	ENST00000372285.8	c.498-421A>C		intron_variant		1	NM_001250.6	ENSP00000361359	P1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 3051 AN: 78600 Hom.: 0 Cov.: 18 FAILED QC

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

Gnomad4 AFR AF: 0.0495

Gnomad4 AMR AF: 0.0295

Gnomad4 ASJ AF: 0.0345

Gnomad4 EAS AF: 0.0102

Gnomad4 SAS AF: 0.0203

Gnomad4 FIN AF: 0.0217

Gnomad4 NFE AF: 0.0420

Gnomad4 OTH AF: 0.0398

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

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

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;