X-136659171-G-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 2P and 13B. PM1BP4_StrongBP6BS1BS2

The NM_000074.3(CD40LG):c.542G>C(p.Arg181Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000686 in 1,209,725 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 19 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R181W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00039 ( 0 hom., 14 hem., cov: 22)

Exomes 𝑓: 0.000036 ( 0 hom. 5 hem. )

Consequence

CD40LG
NM_000074.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: -0.340

Publications

6 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 -11 ACMG points.

PM1

In a chain CD40 ligand, soluble form (size 148) in uniprot entity CD40L_HUMAN there are 33 pathogenic changes around while only 12 benign (73%) in NM_000074.3

BP4

Computational evidence support a benign effect (MetaRNN=0.041614532).

BP6

Variant X-136659171-G-C is Benign according to our data. Variant chrX-136659171-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 439470.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000393 (44/111870) while in subpopulation AFR AF = 0.00137 (42/30760). AF 95% confidence interval is 0.00104. There are 0 homozygotes in GnomAd4. There are 14 alleles in the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check.

BS2

High Hemizygotes in GnomAd4 at 14 XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000074.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CD40LG	NM_000074.3	MANE Select	c.542G>C	p.Arg181Pro	missense	Exon 5 of 5	NP_000065.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CD40LG	ENST00000370629.7	TSL:1 MANE Select	c.542G>C	p.Arg181Pro	missense	Exon 5 of 5	ENSP00000359663.2
CD40LG	ENST00000370628.2	TSL:1	c.479G>C	p.Arg160Pro	missense	Exon 4 of 4	ENSP00000359662.2
CD40LG	ENST00000695724.1		c.*160G>C		3_prime_UTR	Exon 4 of 4	ENSP00000512122.1

Frequencies

GnomAD3 genomes

AF:

0.000393

AC:

AN:

111870

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00137

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000948

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000188

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000928

AC:

AN:

183179

AF XY:

0.0000443

show subpopulations

Gnomad AFR exome

AF:

0.00122

Gnomad AMR exome

AF:

0.0000365

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000355

AC:

AN:

1097855

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

363215

show subpopulations

African (AFR)

AF:

0.00125

AC:

AN:

26395

American (AMR)

AF:

0.0000568

AC:

AN:

35207

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19382

East Asian (EAS)

AF:

0.00

AC:

AN:

30203

South Asian (SAS)

AF:

0.00

AC:

AN:

54141

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40531

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4136

European-Non Finnish (NFE)

AF:

0.00000119

AC:

AN:

841774

Other (OTH)

AF:

0.0000651

AC:

AN:

46086

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<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:

0.000393

AC:

AN:

111870

Hom.:

Cov.:

AF XY:

0.000411

AC XY:

AN XY:

34024

show subpopulations

African (AFR)

AF:

0.00137

AC:

AN:

30760

American (AMR)

AF:

0.0000948

AC:

AN:

10552

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2646

East Asian (EAS)

AF:

0.00

AC:

AN:

3581

South Asian (SAS)

AF:

0.00

AC:

AN:

2675

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6068

Middle Eastern (MID)

AF:

0.00

AC:

AN:

239

European-Non Finnish (NFE)

AF:

0.0000188

AC:

AN:

53168

Other (OTH)

AF:

0.00

AC:

AN:

1501

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.00

Hom.:

Bravo

AF:

0.000442

ESP6500AA

AF:

0.00104

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000140

AC:

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hyper-IgM syndrome type 1 (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.25

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.72

FATHMM_MKL

Benign

0.042

LIST_S2

Benign

0.80

M_CAP

Pathogenic

0.66

MetaRNN

Benign

0.042

MetaSVM

Uncertain

0.064

MutationAssessor

Uncertain

2.4

PhyloP100

-0.34

PrimateAI

Benign

0.25

PROVEAN

Benign

-1.4

REVEL

Uncertain

0.35

Sift

Uncertain

0.024

Sift4G

Benign

0.22

Polyphen

0.93

Vest4

0.065

MVP

0.68

MPC

0.73

ClinPred

0.028

GERP RS

1.9

Varity_R

0.74

gMVP

0.68

Mutation Taster

=86/14

polymorphism

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over