dbSNP rs3092923: CD40LG:c.410-13T>C (chrX-136659026-T-C) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000074.3(CD40LG):c.410-13T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.13 in 1,206,594 control chromosomes in the GnomAD database, including 15,267 homozygotes. There are 50,475 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.27 ( 5848 hom., 8327 hem., cov: 22)

Exomes 𝑓: 0.12 ( 9419 hom. 42148 hem. )

Consequence

CD40LG
NM_000074.3 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -0.331

Publications

17 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: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen

CD40LG 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=-0.9).

BP6

Variant X-136659026-T-C is Benign according to our data. Variant chrX-136659026-T-C is described in ClinVar as Benign. ClinVar VariationId is 518407.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.689 is higher than 0.05.

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.410-13T>C		intron	N/A	NP_000065.1	P29965

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
CD40LG	ENST00000370629.7	TSL:1 MANE Select	c.410-13T>C	intron	N/A	ENSP00000359663.2	P29965
CD40LG	ENST00000370628.2	TSL:1	c.347-13T>C	intron	N/A	ENSP00000359662.2	Q3L8U2
CD40LG	ENST00000695724.1		c.*28-13T>C	intron	N/A	ENSP00000512122.1	A0A8Q3WKP2

Frequencies

GnomAD3 genomes

AF:

0.267

AC:

29594

AN:

110768

Hom.:

5844

Cov.:

show subpopulations

Gnomad AFR

AF:

0.697

Gnomad AMI

AF:

0.00438

Gnomad AMR

AF:

0.178

Gnomad ASJ

AF:

0.138

Gnomad EAS

AF:

0.101

Gnomad SAS

AF:

0.225

Gnomad FIN

AF:

0.0652

Gnomad MID

AF:

0.228

Gnomad NFE

AF:

0.0858

Gnomad OTH

AF:

0.240

GnomAD2 exomes

AF:

0.167

AC:

30241

AN:

181473

AF XY:

0.156

show subpopulations

Gnomad AFR exome

AF:

0.715

Gnomad AMR exome

AF:

0.180

Gnomad ASJ exome

AF:

0.128

Gnomad EAS exome

AF:

0.104

Gnomad FIN exome

AF:

0.0745

Gnomad NFE exome

AF:

0.0901

Gnomad OTH exome

AF:

0.154

GnomAD4 exome

AF:

0.116

AC:

126805

AN:

1095772

Hom.:

9419

Cov.:

AF XY:

0.117

AC XY:

42148

AN XY:

361532

show subpopulations

African (AFR)

AF:

0.726

AC:

19119

AN:

26331

American (AMR)

AF:

0.182

AC:

6410

AN:

35197

Ashkenazi Jewish (ASJ)

AF:

0.128

AC:

2469

AN:

19362

East Asian (EAS)

AF:

0.116

AC:

3501

AN:

30199

South Asian (SAS)

AF:

0.234

AC:

12646

AN:

54086

European-Finnish (FIN)

AF:

0.0755

AC:

3045

AN:

40339

Middle Eastern (MID)

AF:

0.229

AC:

943

AN:

4126

European-Non Finnish (NFE)

AF:

0.0852

AC:

71601

AN:

840115

Other (OTH)

AF:

0.154

AC:

7071

AN:

46017

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

3405

6810

10216

13621

17026

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3054

6108

9162

12216

15270

<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:

0.268

AC:

29654

AN:

110822

Hom.:

5848

Cov.:

AF XY:

0.250

AC XY:

8327

AN XY:

33360

show subpopulations

African (AFR)

AF:

0.697

AC:

21124

AN:

30312

American (AMR)

AF:

0.178

AC:

1868

AN:

10503

Ashkenazi Jewish (ASJ)

AF:

0.138

AC:

364

AN:

2633

East Asian (EAS)

AF:

0.101

AC:

359

AN:

3542

South Asian (SAS)

AF:

0.226

AC:

596

AN:

2641

European-Finnish (FIN)

AF:

0.0652

AC:

393

AN:

6023

Middle Eastern (MID)

AF:

0.241

AC:

AN:

212

European-Non Finnish (NFE)

AF:

0.0858

AC:

4526

AN:

52756

Other (OTH)

AF:

0.244

AC:

370

AN:

1515

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

519

1038

1556

2075

2594

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

260

520

780

1040

1300

<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:

0.187

Hom.:

2122

Bravo

AF:

0.298

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Hyper-IgM syndrome type 1 (2)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

1.1

(source)

DANN

Benign

0.48

PhyloP100

-0.33

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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