20-46129175-C-G

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.*135C>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0415 in 962,462 control chromosomes in the GnomAD database, including 1,040 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.036 ( 149 hom., cov: 32)

Exomes 𝑓: 0.042 ( 891 hom. )

Consequence

CD40
NM_001250.6 3_prime_UTR

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.169

Publications

7 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: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae)

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 20-46129175-C-G is Benign according to our data. Variant chr20-46129175-C-G is described in ClinVar as Benign. ClinVar VariationId is 338579.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0525 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	UniProt
CD40	NM_001250.6	MANE Select	c.*135C>G	3_prime_UTR	Exon 9 of 9	NP_001241.1	P25942-1
CD40	NM_001322421.2		c.*135C>G	3_prime_UTR	Exon 9 of 9	NP_001309350.1
CD40	NM_001302753.2		c.*295C>G	3_prime_UTR	Exon 9 of 9	NP_001289682.1	A0A8Q3SI60

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
CD40	ENST00000372285.8	TSL:1 MANE Select	c.*135C>G	3_prime_UTR	Exon 9 of 9	ENSP00000361359.3	P25942-1
CD40	ENST00000372276.7	TSL:1	c.*295C>G	3_prime_UTR	Exon 8 of 8	ENSP00000361350.3	P25942-2
CD40	ENST00000620709.4	TSL:1	n.*516C>G	non_coding_transcript_exon	Exon 7 of 7	ENSP00000484074.1	A0A087X1D0

Frequencies

GnomAD3 genomes

AF:

0.0360

AC:

5485

AN:

152190

Hom.:

149

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00970

Gnomad AMI

AF:

0.0450

Gnomad AMR

AF:

0.0243

Gnomad ASJ

AF:

0.0377

Gnomad EAS

AF:

0.000962

Gnomad SAS

AF:

0.0207

Gnomad FIN

AF:

0.0648

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.0540

Gnomad OTH

AF:

0.0344

GnomAD2 exomes

AF:

0.0371

AC:

6047

AN:

162882

AF XY:

0.0377

show subpopulations

Gnomad AFR exome

AF:

0.00966

Gnomad AMR exome

AF:

0.0184

Gnomad ASJ exome

AF:

0.0364

Gnomad EAS exome

AF:

0.000162

Gnomad FIN exome

AF:

0.0665

Gnomad NFE exome

AF:

0.0552

Gnomad OTH exome

AF:

0.0422

GnomAD4 exome

AF:

0.0425

AC:

34426

AN:

810156

Hom.:

891

Cov.:

AF XY:

0.0419

AC XY:

17725

AN XY:

423042

show subpopulations

African (AFR)

AF:

0.00915

AC:

192

AN:

20980

American (AMR)

AF:

0.0188

AC:

685

AN:

36474

Ashkenazi Jewish (ASJ)

AF:

0.0371

AC:

801

AN:

21618

East Asian (EAS)

AF:

0.0000587

AC:

AN:

34066

South Asian (SAS)

AF:

0.0243

AC:

1688

AN:

69390

European-Finnish (FIN)

AF:

0.0649

AC:

2359

AN:

36350

Middle Eastern (MID)

AF:

0.0350

AC:

144

AN:

4110

European-Non Finnish (NFE)

AF:

0.0492

AC:

26981

AN:

547930

Other (OTH)

AF:

0.0401

AC:

1574

AN:

39238

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1679

3358

5037

6716

8395

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

552

1104

1656

2208

2760

<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:

0.0360

AC:

5483

AN:

152306

Hom.:

149

Cov.:

AF XY:

0.0354

AC XY:

2637

AN XY:

74472

show subpopulations

African (AFR)

AF:

0.00969

AC:

403

AN:

41572

American (AMR)

AF:

0.0242

AC:

371

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.0377

AC:

131

AN:

3472

East Asian (EAS)

AF:

0.000964

AC:

AN:

5188

South Asian (SAS)

AF:

0.0205

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.0648

AC:

687

AN:

10610

Middle Eastern (MID)

AF:

0.0204

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0539

AC:

3668

AN:

68016

Other (OTH)

AF:

0.0341

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

271

542

814

1085

1356

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

128

192

256

320

<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:

0.0456

Hom.:

Bravo

AF:

0.0312

Asia WGS

AF:

0.00866

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Hyper-IgM syndrome type 3 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

0.86

(source)

DANN

Benign

0.59

PhyloP100

-0.17

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

Computational scores

Splicing

Publications

Other links and lift over