rs148594123

Variant names:

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBS1BS2

The NM_000074.3(CD40LG):c.655G>A(p.Gly219Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.015 in 1,209,678 control chromosomes in the GnomAD database, including 122 homozygotes. There are 5,855 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.010 ( 6 hom., 336 hem., cov: 23)

Exomes 𝑓: 0.016 ( 116 hom. 5519 hem. )

Consequence

CD40LG
NM_000074.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 1.41

Publications

25 publications found

Variant links:

Genes affected

CD40LG (HGNC:11935): (CD40 ligand) The protein encoded by this gene is expressed on the surface of T cells. It regulates B cell function by engaging CD40 on the B cell surface. A defect in this gene results in an inability to undergo immunoglobulin class switch and is associated with hyper-IgM syndrome. [provided by RefSeq, Jul 2008]

CD40LG Gene-Disease associations (from GenCC):

hyper-IgM syndrome type 1
Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics, ClinGen

CD40LG links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -18 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_000074.3

BP4

Computational evidence support a benign effect (MetaRNN=0.006652802).

BP6

Variant X-136659284-G-A is Benign according to our data. Variant chrX-136659284-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 35813.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.01 (1122/112015) while in subpopulation NFE AF = 0.0151 (801/53154). AF 95% confidence interval is 0.0142. There are 6 homozygotes in GnomAd4. There are 336 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 6 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CD40LG	NM_000074.3 link	c.655G>A	p.Gly219Arg	missense_variant	Exon 5 of 5	ENST00000370629.7	NP_000065.1	P29965

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CD40LG	ENST00000370629.7 link	c.655G>A	p.Gly219Arg	missense_variant	Exon 5 of 5	1	NM_000074.3	ENSP00000359663.2		P29965

Frequencies

GnomAD3 genomes

AF:

0.0100

AC:

1120

AN:

111961

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00260

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00613

Gnomad ASJ

AF:

0.00340

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00295

Gnomad FIN

AF:

0.0247

Gnomad MID

AF:

0.00418

Gnomad NFE

AF:

0.0150

Gnomad OTH

AF:

0.00468

GnomAD2 exomes

AF:

0.0111

AC:

2024

AN:

182591

AF XY:

0.0109

show subpopulations

Gnomad AFR exome

AF:

0.00198

Gnomad AMR exome

AF:

0.00270

Gnomad ASJ exome

AF:

0.00391

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0248

Gnomad NFE exome

AF:

0.0167

Gnomad OTH exome

AF:

0.00800

GnomAD4 exome

AF:

0.0156

AC:

17075

AN:

1097663

Hom.:

116

Cov.:

AF XY:

0.0152

AC XY:

5519

AN XY:

363053

show subpopulations

African (AFR)

AF:

0.00171

AC:

AN:

26391

American (AMR)

AF:

0.00301

AC:

106

AN:

35188

Ashkenazi Jewish (ASJ)

AF:

0.00258

AC:

AN:

19360

East Asian (EAS)

AF:

0.0000662

AC:

AN:

30199

South Asian (SAS)

AF:

0.00608

AC:

329

AN:

54087

European-Finnish (FIN)

AF:

0.0245

AC:

991

AN:

40521

Middle Eastern (MID)

AF:

0.00387

AC:

AN:

4135

European-Non Finnish (NFE)

AF:

0.0178

AC:

15021

AN:

841699

Other (OTH)

AF:

0.0112

AC:

515

AN:

46083

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

644

1288

1933

2577

3221

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

574

1148

1722

2296

2870

<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:

0.0100

AC:

1122

AN:

112015

Hom.:

Cov.:

AF XY:

0.00982

AC XY:

336

AN XY:

34223

show subpopulations

African (AFR)

AF:

0.00259

AC:

AN:

30863

American (AMR)

AF:

0.00613

AC:

AN:

10608

Ashkenazi Jewish (ASJ)

AF:

0.00340

AC:

AN:

2645

East Asian (EAS)

AF:

0.00

AC:

AN:

3561

South Asian (SAS)

AF:

0.00333

AC:

AN:

2700

European-Finnish (FIN)

AF:

0.0247

AC:

150

AN:

6063

Middle Eastern (MID)

AF:

0.00459

AC:

AN:

218

European-Non Finnish (NFE)

AF:

0.0151

AC:

801

AN:

53154

Other (OTH)

AF:

0.00462

AC:

AN:

1516

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

118

157

196

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.0127

Hom.:

682

Bravo

AF:

0.00832

TwinsUK

AF:

0.0183

AC:

ALSPAC

AF:

0.0222

AC:

ESP6500AA

AF:

0.00261

AC:

ESP6500EA

AF:

0.0171

AC:

115

ExAC

AF:

0.0113

AC:

1372

EpiCase

AF:

0.0141

EpiControl

AF:

0.0133

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Jul 20, 2016

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 08, 2016

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: The CD40LG c.655G>A variant affects a non-conserved nucleotide, resulting in amino acid change from Gly to Arg. 3/5 in-silico tools predict this variant to be damaging. In vitro functional studies suggest that G219R has decreased ligand binding and decreased capacity to activate B cells. However, the single expression of G219R protein has no or only minor effects in vivo as shown by an asymptomatic carrier of G219R who has normal values of serum IgA and IgM and normal B-cell subpopulations (Rigaud 2011). These functional studies suggest that this variant is a functional polymorphism.This variant was found in 992/88003 control chromosomes (at least 7 homozygotes and 388 hemizygotes) at a frequency of 0.0112723, which is about 7 times the maximal expected frequency of a pathogenic CD40LG allele (0.0015811) for HIGM1, suggesting this variant is benign. The variant has been reported in patients with hyper IgM syndrome, non-X-linked HIGM, X-linked variable immunodeficiency, and hypogammaglobulinemia, However, some of these patients had other probable disease causing mutations in cis (Gln232X; Lin 1996) or in another gene (XIAP G466X; Rigaud 2011), or unaffected compound heterozygous or hemizygous family members (lack of segregation with disease; Martinez-Martinez 2012 and Rigaud 2011), suggesting that this variant itself is not pathogenic in isolation. Taken together, this variant is not disease causing in isolation but may play a contributory role in certain backgrounds, and therefore is classified as benign. -

Hyper-IgM syndrome type 1

Benign:2

Oct 09, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.40

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Pathogenic

0.91

D;D

FATHMM_MKL

Benign

0.10

LIST_S2

Benign

0.72

T;T

MetaRNN

Benign

0.0067

T;T

MetaSVM

Uncertain

-0.0033

MutationAssessor

Benign

1.9

L;.

PhyloP100

1.4

PrimateAI

Benign

0.37

PROVEAN

Uncertain

-2.8

D;D

REVEL

Benign

0.22

Sift

Uncertain

0.014

D;D

Sift4G

Benign

0.069

T;T

Polyphen

0.43

B;D

Vest4

0.054

MutPred

0.44

Loss of ubiquitination at K216 (P = 0.0312);.;

MPC

0.63

ClinPred

0.027

GERP RS

2.7

Varity_R

0.44

gMVP

0.76

Mutation Taster

=89/11

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over