NM_001250.6:c.679C>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.679C>G(p.Pro227Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0104 in 1,614,024 control chromosomes in the GnomAD database, including 523 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Synonymous variant affecting the same amino acid position (i.e. P227P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.015 ( 112 hom., cov: 32)

Exomes 𝑓: 0.0099 ( 411 hom. )

Consequence

CD40
NM_001250.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -1.61

Publications

25 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 (MetaRNN=0.0016620457).

BP6

Variant 20-46128885-C-G is Benign according to our data. Variant chr20-46128885-C-G is described in ClinVar as Benign. ClinVar VariationId is 338576.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0964 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CD40	NM_001250.6 link	c.679C>G	p.Pro227Ala	missense_variant	Exon 9 of 9	ENST00000372285.8	NP_001241.1	P25942-1A0A0S2Z3C7Q6P2H9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CD40	ENST00000372285.8 link	c.679C>G	p.Pro227Ala	missense_variant	Exon 9 of 9	1	NM_001250.6	ENSP00000361359.3		P25942-1

Frequencies

GnomAD3 genomes

AF:

0.0152

AC:

2307

AN:

152140

Hom.:

112

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00413

Gnomad AMI

AF:

0.0329

Gnomad AMR

AF:

0.100

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00231

Gnomad SAS

AF:

0.00580

Gnomad FIN

AF:

0.00113

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00715

Gnomad OTH

AF:

0.0154

GnomAD2 exomes

AF:

0.0218

AC:

5462

AN:

250810

AF XY:

0.0176

show subpopulations

Gnomad AFR exome

AF:

0.00351

Gnomad AMR exome

AF:

0.123

Gnomad ASJ exome

AF:

0.000497

Gnomad EAS exome

AF:

0.00266

Gnomad FIN exome

AF:

0.00171

Gnomad NFE exome

AF:

0.00693

Gnomad OTH exome

AF:

0.0199

GnomAD4 exome

AF:

0.00993

AC:

14513

AN:

1461766

Hom.:

411

Cov.:

AF XY:

0.00937

AC XY:

6811

AN XY:

727178

show subpopulations

African (AFR)

AF:

0.00260

AC:

AN:

33480

American (AMR)

AF:

0.121

AC:

5400

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.000497

AC:

AN:

26136

East Asian (EAS)

AF:

0.00242

AC:

AN:

39700

South Asian (SAS)

AF:

0.00443

AC:

382

AN:

86258

European-Finnish (FIN)

AF:

0.00187

AC:

100

AN:

53392

Middle Eastern (MID)

AF:

0.00260

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00702

AC:

7804

AN:

1111930

Other (OTH)

AF:

0.0102

AC:

616

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

740

1480

2220

2960

3700

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

344

688

1032

1376

1720

<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:

0.0152

AC:

2311

AN:

152258

Hom.:

112

Cov.:

AF XY:

0.0167

AC XY:

1242

AN XY:

74444

show subpopulations

African (AFR)

AF:

0.00412

AC:

171

AN:

41544

American (AMR)

AF:

0.101

AC:

1539

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00232

AC:

AN:

5178

South Asian (SAS)

AF:

0.00581

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00113

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00715

AC:

486

AN:

68008

Other (OTH)

AF:

0.0152

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

109

218

327

436

545

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

110

<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:

0.00772

Hom.:

Bravo

AF:

0.0216

TwinsUK

AF:

0.00701

AC:

ALSPAC

AF:

0.00727

AC:

ESP6500AA

AF:

0.00386

AC:

ESP6500EA

AF:

0.00802

AC:

ExAC

AF:

0.0170

AC:

2068

Asia WGS

AF:

0.00924

AC:

AN:

3478

EpiCase

AF:

0.00622

EpiControl

AF:

0.00688

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hyper-IgM syndrome type 3

Benign:2

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Nov 08, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

May 16, 2016

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.064

BayesDel_addAF

Benign

-0.63

BayesDel_noAF

Benign

-0.58

CADD

Benign

0.0010

(source)

DANN

Benign

0.42

DEOGEN2

Benign

0.20

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.053

LIST_S2

Benign

0.39

MetaRNN

Benign

0.0017

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.2

PhyloP100

-1.6

PrimateAI

Benign

0.21

PROVEAN

Benign

-0.070

REVEL

Benign

0.077

Sift

Benign

0.51

Sift4G

Benign

0.58

Polyphen

0.0030

Vest4

0.020

MPC

0.45

ClinPred

0.0035

GERP RS

-4.9

Varity_R

0.024

gMVP

0.16

Mutation Taster

=99/1

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over