rs3765456

chr20-46128252-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.646+28G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.124 in 1,612,390 control chromosomes in the GnomAD database, including 14,445 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (1444 hom., cov: 29)
  • Exomes 𝑓: 0.12 (13001 hom.)
• Consequence: CD40 NM_001250.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.143

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=-0.81).
• BP6: Variant 20-46128252-G-A is Benign according to our data. Variant chr20-46128252-G-A is described in ClinVar as [Benign]. Clinvar id is 1267312.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.403 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CD40	NM_001250.6	c.646+28G>A		intron_variant		ENST00000372285.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CD40	ENST00000372285.8	c.646+28G>A		intron_variant		1	NM_001250.6	P1

Frequencies

GnomAD3 genomes AF: 0.124 AC: 18670 AN: 150980 Hom.: 1447 Cov.: 29

Gnomad AFR AF: 0.106

Gnomad AMI AF: 0.166

Gnomad AMR AF: 0.115

Gnomad ASJ AF: 0.0667

Gnomad EAS AF: 0.418

Gnomad SAS AF: 0.173

Gnomad FIN AF: 0.119

Gnomad MID AF: 0.114

Gnomad NFE AF: 0.114

Gnomad OTH AF: 0.119

GnomAD3 exomes AF: 0.144 AC: 36089 AN: 251436 Hom.: 3533 AF XY: 0.143 AC XY: 19475 AN XY: 135898

Gnomad AFR exome AF: 0.109

Gnomad AMR exome AF: 0.119

Gnomad ASJ exome AF: 0.0750

Gnomad EAS exome AF: 0.438

Gnomad SAS exome AF: 0.161

Gnomad FIN exome AF: 0.134

Gnomad NFE exome AF: 0.113

Gnomad OTH exome AF: 0.124

GnomAD4 exome AF: 0.124 AC: 180592 AN: 1461312 Hom.: 13001 Cov.: 35 AF XY: 0.125 AC XY: 90613 AN XY: 726982

Gnomad4 AFR exome AF: 0.107

Gnomad4 AMR exome AF: 0.118

Gnomad4 ASJ exome AF: 0.0699

Gnomad4 EAS exome AF: 0.375

Gnomad4 SAS exome AF: 0.160

Gnomad4 FIN exome AF: 0.136

Gnomad4 NFE exome AF: 0.113

Gnomad4 OTH exome AF: 0.137

GnomAD4 genome AF: 0.124 AC: 18674 AN: 151078 Hom.: 1444 Cov.: 29 AF XY: 0.126 AC XY: 9276 AN XY: 73724

Gnomad4 AFR AF: 0.106

Gnomad4 AMR AF: 0.115

Gnomad4 ASJ AF: 0.0667

Gnomad4 EAS AF: 0.418

Gnomad4 SAS AF: 0.173

Gnomad4 FIN AF: 0.119

Gnomad4 NFE AF: 0.114

Gnomad4 OTH AF: 0.118

Alfa AF: 0.111 Hom.: 187

Bravo AF: 0.124

Asia WGS AF: 0.234 AC: 810 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 24% of patients studied by a panel of primary immunodeficiencies. Number of patients: 23. Only high quality variants are reported. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 10, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
Cadd	Benign	3.1
Dann	Benign	0.65

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs3765456; hg19: chr20-44756891; COSMIC: COSV64847830; COSMIC: COSV64847830;