20-46128768-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.676-114G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.225 in 1,156,138 control chromosomes in the GnomAD database, including 31,272 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.18 ( 3061 hom., cov: 31)

Exomes 𝑓: 0.23 ( 28211 hom. )

Consequence

CD40
NM_001250.6 intron

Scores

Clinical Significance

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

Conservation

PhyloP100: -1.97

Publications

33 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=-0.96).

BP6

Variant 20-46128768-G-A is Benign according to our data. Variant chr20-46128768-G-A is described in ClinVar as Benign. ClinVar VariationId is 1261840.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.28 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.676-114G>A	intron	N/A	NP_001241.1
CD40	NM_001322421.2		c.688-114G>A	intron	N/A	NP_001309350.1
CD40	NM_001302753.2		c.*2-114G>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.676-114G>A	intron	N/A	ENSP00000361359.3
CD40	ENST00000372276.7	TSL:1	c.*2-114G>A	intron	N/A	ENSP00000361350.3
CD40	ENST00000466205.5	TSL:1	n.*99-114G>A	intron	N/A	ENSP00000434825.1

Frequencies

GnomAD3 genomes

AF:

0.184

AC:

27985

AN:

151880

Hom.:

3056

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0627

Gnomad AMI

AF:

0.355

Gnomad AMR

AF:

0.157

Gnomad ASJ

AF:

0.228

Gnomad EAS

AF:

0.292

Gnomad SAS

AF:

0.264

Gnomad FIN

AF:

0.246

Gnomad MID

AF:

0.237

Gnomad NFE

AF:

0.236

Gnomad OTH

AF:

0.179

GnomAD2 exomes

AF:

0.220

AC:

35321

AN:

160452

AF XY:

0.228

show subpopulations

Gnomad AFR exome

AF:

0.0581

Gnomad AMR exome

AF:

0.122

Gnomad ASJ exome

AF:

0.229

Gnomad EAS exome

AF:

0.308

Gnomad FIN exome

AF:

0.251

Gnomad NFE exome

AF:

0.243

Gnomad OTH exome

AF:

0.224

GnomAD4 exome

AF:

0.231

AC:

231901

AN:

1004140

Hom.:

28211

Cov.:

AF XY:

0.233

AC XY:

119087

AN XY:

510964

show subpopulations

African (AFR)

AF:

0.0599

AC:

1479

AN:

24698

American (AMR)

AF:

0.125

AC:

4577

AN:

36734

Ashkenazi Jewish (ASJ)

AF:

0.230

AC:

4817

AN:

20926

East Asian (EAS)

AF:

0.286

AC:

10075

AN:

35282

South Asian (SAS)

AF:

0.268

AC:

18529

AN:

69182

European-Finnish (FIN)

AF:

0.249

AC:

10308

AN:

41468

Middle Eastern (MID)

AF:

0.247

AC:

1201

AN:

4864

European-Non Finnish (NFE)

AF:

0.236

AC:

171008

AN:

726040

Other (OTH)

AF:

0.220

AC:

9907

AN:

44946

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

9569

19137

28706

38274

47843

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4824

9648

14472

19296

24120

<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:

0.184

AC:

27995

AN:

151998

Hom.:

3061

Cov.:

AF XY:

0.186

AC XY:

13800

AN XY:

74272

show subpopulations

African (AFR)

AF:

0.0629

AC:

2607

AN:

41476

American (AMR)

AF:

0.157

AC:

2393

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.228

AC:

790

AN:

3466

East Asian (EAS)

AF:

0.293

AC:

1508

AN:

5154

South Asian (SAS)

AF:

0.265

AC:

1273

AN:

4806

European-Finnish (FIN)

AF:

0.246

AC:

2595

AN:

10568

Middle Eastern (MID)

AF:

0.231

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.236

AC:

16063

AN:

67942

Other (OTH)

AF:

0.179

AC:

376

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

1112

2225

3337

4450

5562

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

314

628

942

1256

1570

<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:

0.207

Hom.:

680

Bravo

AF:

0.173

Asia WGS

AF:

0.228

AC:

794

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

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Aug 08, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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 21% of patients studied by a panel of primary immunodeficiencies. Number of patients: 20. Only high quality variants are reported.

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.96

CADD

Benign

0.077

(source)

DANN

Benign

0.75

PhyloP100

-2.0

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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