20-46118447-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001250.6(CD40):c.51+53G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.253 in 1,443,336 control chromosomes in the GnomAD database, including 46,725 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.18 (2950 hom., cov: 32)
  • Exomes 𝑓: 0.26 (43775 hom.)
• Consequence: CD40 NM_001250.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.382

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 20-46118447-G-A is Benign according to our data. Variant chr20-46118447-G-A is described in ClinVar as [Benign]. Clinvar id is 1245520.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.255 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CD40	NM_001250.6	c.51+53G>A		intron_variant		ENST00000372285.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CD40	ENST00000372285.8	c.51+53G>A		intron_variant		1	NM_001250.6	P1

Frequencies

GnomAD3 genomes AF: 0.180 AC: 26856 AN: 149476 Hom.: 2949 Cov.: 32

Gnomad AFR AF: 0.0653

Gnomad AMI AF: 0.237

Gnomad AMR AF: 0.126

Gnomad ASJ AF: 0.186

Gnomad EAS AF: 0.0337

Gnomad SAS AF: 0.183

Gnomad FIN AF: 0.259

Gnomad MID AF: 0.178

Gnomad NFE AF: 0.258

Gnomad OTH AF: 0.187

GnomAD4 exome AF: 0.262 AC: 338338 AN: 1293722 Hom.: 43775 AF XY: 0.261 AC XY: 168537 AN XY: 645632

Gnomad4 AFR exome AF: 0.0690

Gnomad4 AMR exome AF: 0.109

Gnomad4 ASJ exome AF: 0.221

Gnomad4 EAS exome AF: 0.0610

Gnomad4 SAS exome AF: 0.189

Gnomad4 FIN exome AF: 0.308

Gnomad4 NFE exome AF: 0.284

Gnomad4 OTH exome AF: 0.248

GnomAD4 genome AF: 0.179 AC: 26853 AN: 149614 Hom.: 2950 Cov.: 32 AF XY: 0.177 AC XY: 12914 AN XY: 73116

Gnomad4 AFR AF: 0.0652

Gnomad4 AMR AF: 0.126

Gnomad4 ASJ AF: 0.186

Gnomad4 EAS AF: 0.0336

Gnomad4 SAS AF: 0.184

Gnomad4 FIN AF: 0.259

Gnomad4 NFE AF: 0.258

Gnomad4 OTH AF: 0.183

Alfa AF: 0.228 Hom.: 4105

Bravo AF: 0.163

Asia WGS AF: 0.100 AC: 349 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Jan 24, 2024

This variant is classified as Benign based on local population frequency. This variant was detected in 28% of patients studied by a panel of primary immunodeficiencies. Number of patients: 27. Only high quality variants are reported. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 08, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
Cadd	Benign	11
Dann	Benign	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

Publications

LitVar

Other links and lift over

dbSNP: rs745307; hg19: chr20-44747086; COSMIC: COSV64847751; COSMIC: COSV64847751;