20-46128252-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.143

Publications

13 publications found

Variant links:

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

CD40 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001250.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
CD40	NM_001250.6	MANE Select	c.646+28G>A	intron	N/A	NP_001241.1
CD40	NM_001322421.2		c.658+16G>A	intron	N/A	NP_001309350.1
CD40	NM_001302753.2		c.686+28G>A	intron	N/A	NP_001289682.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
CD40	ENST00000372285.8	TSL:1 MANE Select	c.646+28G>A	intron	N/A	ENSP00000361359.3
CD40	ENST00000372276.7	TSL:1	c.584+28G>A	intron	N/A	ENSP00000361350.3
CD40	ENST00000466205.5	TSL:1	n.*69+28G>A	intron	N/A	ENSP00000434825.1

Frequencies

GnomAD3 genomes

AF:

0.124

AC:

18670

AN:

150980

Hom.:

1447

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.125

AC XY:

90613

AN XY:

726982

show subpopulations

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

9113

18225

27338

36450

45563

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4734

9468

14202

18936

23670

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.124

AC:

18674

AN:

151078

Hom.:

1444

Cov.:

AF XY:

0.126

AC XY:

9276

AN XY:

73724

show subpopulations

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:

AN:

292

European-Non Finnish (NFE)

AF:

0.114

AC:

7721

AN:

67852

Other (OTH)

AF:

0.118

AC:

246

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

744

1488

2233

2977

3721

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

214

428

642

856

1070

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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

LINK: link

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 v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

3.1

(source)

DANN

Benign

0.65

PhyloP100

0.14

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over