20-46128252-G-A

Variant names:

• chr20-46128252-G-A
• rs3765456
• NM_001250.6:c.646+28G>A

Variant summary

Our verdict is Benign. The variant received -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:3
• Conservation: PhyloP100: 0.143
• Publications: 13 publications found

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]

CD40 Gene-Disease associations (from GenCC):

• hyper-IgM syndrome type 3

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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 rank	MANE	Protein	UniProt
CD40	NM_001250.6	c.646+28G>A		intron_variant	Intron 7 of 8	ENST00000372285.8	NP_001241.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CD40	ENST00000372285.8	c.646+28G>A		intron_variant	Intron 7 of 8	1	NM_001250.6	ENSP00000361359.3

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

GnomAD2 exomes AF: 0.144 AC: 36089 AN: 251436 AF XY: 0.143

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 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

African (AFR) AF: 0.107 AC: 3591 AN: 33468

American (AMR) AF: 0.118 AC: 5266 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0699 AC: 1826 AN: 26136

East Asian (EAS) AF: 0.375 AC: 14894 AN: 39688

South Asian (SAS) AF: 0.160 AC: 13763 AN: 86244

European-Finnish (FIN) AF: 0.136 AC: 7242 AN: 53416

Middle Eastern (MID) AF: 0.115 AC: 666 AN: 5768

European-Non Finnish (NFE) AF: 0.113 AC: 125089 AN: 1111496

Other (OTH) AF: 0.137 AC: 8255 AN: 60376

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

African (AFR) AF: 0.106 AC: 4368 AN: 41064

American (AMR) AF: 0.115 AC: 1741 AN: 15184

Ashkenazi Jewish (ASJ) AF: 0.0667 AC: 231 AN: 3464

East Asian (EAS) AF: 0.418 AC: 2125 AN: 5084

South Asian (SAS) AF: 0.173 AC: 825 AN: 4774

European-Finnish (FIN) AF: 0.119 AC: 1233 AN: 10366

Middle Eastern (MID) AF: 0.113 AC: 33 AN: 292

European-Non Finnish (NFE) AF: 0.114 AC: 7721 AN: 67852

Other (OTH) AF: 0.118 AC: 246 AN: 2090

Alfa AF: 0.111 Hom.: 190

Bravo AF: 0.124

Asia WGS AF: 0.234 AC: 810 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Nov 10, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:1

Jan 24, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	3.1
DANN	Benign	0.65
PhyloP100		0.14
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3765456; hg19: chr20-44756891; COSMIC: COSV64847830; COSMIC: COSV64847830;