rs11569343

Variant names:

• chr20-46129175-C-G
• rs11569343
• ENST00000620709.4:n.*516C>G

Your query was ambiguous. Multiple possible variants found:

• chr20-46129175-C-G
• chr20-46129175-C-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000620709.4(CD40):​n.*516C>G variant causes a non coding transcript exon 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 ENST00000620709.4 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.169
• Publications: 7 publications found

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

ACMG classification

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CD40	NM_001250.6	c.*135C>G		3_prime_UTR_variant	Exon 9 of 9	ENST00000372285.8	NP_001241.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CD40	ENST00000372285.8	c.*135C>G		3_prime_UTR_variant	Exon 9 of 9	1	NM_001250.6	ENSP00000361359.3

Frequencies

GnomAD3 genomes AF: 0.0360 AC: 5485 AN: 152190 Hom.: 149 Cov.: 32

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

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.: 11 AF XY: 0.0419 AC XY: 17725 AN XY: 423042

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: 2 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

GnomAD4 genome AF: 0.0360 AC: 5483 AN: 152306 Hom.: 149 Cov.: 32 AF XY: 0.0354 AC XY: 2637 AN XY: 74472

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: 5 AN: 5188

South Asian (SAS) AF: 0.0205 AC: 99 AN: 4826

European-Finnish (FIN) AF: 0.0648 AC: 687 AN: 10610

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.0539 AC: 3668 AN: 68016

Other (OTH) AF: 0.0341 AC: 72 AN: 2112

Alfa AF: 0.0456 Hom.: 38

Bravo AF: 0.0312

Asia WGS AF: 0.00866 AC: 30 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

May 12, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Hyper-IgM syndrome type 3 Benign:1

Jan 13, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.86
DANN	Benign	0.59
PhyloP100		-0.17
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs11569343; hg19: chr20-44757814;