20-46118343-T-C

Variant names:

• chr20-46118343-T-C
• rs1883832
• ENST00000620709.4:n.-1T>C

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.-1T>C 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 0.754 in 1,613,190 control chromosomes in the GnomAD database, including 461,294 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.79 (48521 hom., cov: 34)
  • Exomes 𝑓: 0.75 (412773 hom.)
• Consequence: CD40 ENST00000620709.4 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.192
• Publications: 292 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=-0.71).
• BP6: Variant 20-46118343-T-C is Benign according to our data. Variant chr20-46118343-T-C is described in ClinVar as Benign. ClinVar VariationId is 338569.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.932 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000620709.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CD40	NM_001250.6	MANE Select	c.-1T>C		5_prime_UTR	Exon 1 of 9	NP_001241.1
	CD40	NR_126502.2		n.30T>C		non_coding_transcript_exon	Exon 1 of 7
	CD40	NR_136327.2		n.30T>C		non_coding_transcript_exon	Exon 1 of 8

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CD40	ENST00000620709.4	TSL:1	n.-1T>C		non_coding_transcript_exon	Exon 1 of 7	ENSP00000484074.1
	CD40	ENST00000372285.8	TSL:1 MANE Select	c.-1T>C		5_prime_UTR	Exon 1 of 9	ENSP00000361359.3
	CD40	ENST00000372276.7	TSL:1	c.-1T>C		5_prime_UTR	Exon 1 of 8	ENSP00000361350.3

Frequencies

GnomAD3 genomes AF: 0.792 AC: 120443 AN: 152090 Hom.: 48449 Cov.: 34

Gnomad AFR AF: 0.939

Gnomad AMI AF: 0.759

Gnomad AMR AF: 0.774

Gnomad ASJ AF: 0.728

Gnomad EAS AF: 0.568

Gnomad SAS AF: 0.736

Gnomad FIN AF: 0.724

Gnomad MID AF: 0.725

Gnomad NFE AF: 0.742

Gnomad OTH AF: 0.763

GnomAD2 exomes AF: 0.748 AC: 187810 AN: 251134 AF XY: 0.743

Gnomad AFR exome AF: 0.944

Gnomad AMR exome AF: 0.803

Gnomad ASJ exome AF: 0.715

Gnomad EAS exome AF: 0.569

Gnomad FIN exome AF: 0.721

Gnomad NFE exome AF: 0.741

Gnomad OTH exome AF: 0.739

GnomAD4 exome AF: 0.750 AC: 1095784 AN: 1460982 Hom.: 412773 Cov.: 47 AF XY: 0.749 AC XY: 544217 AN XY: 726826

African (AFR) AF: 0.947 AC: 31709 AN: 33472

American (AMR) AF: 0.803 AC: 35918 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.721 AC: 18832 AN: 26120

East Asian (EAS) AF: 0.593 AC: 23536 AN: 39694

South Asian (SAS) AF: 0.748 AC: 64510 AN: 86230

European-Finnish (FIN) AF: 0.725 AC: 38681 AN: 53328

Middle Eastern (MID) AF: 0.705 AC: 3940 AN: 5592

European-Non Finnish (NFE) AF: 0.750 AC: 833877 AN: 1111466

Other (OTH) AF: 0.742 AC: 44781 AN: 60356

GnomAD4 genome AF: 0.792 AC: 120577 AN: 152208 Hom.: 48521 Cov.: 34 AF XY: 0.787 AC XY: 58533 AN XY: 74408

African (AFR) AF: 0.940 AC: 39056 AN: 41566

American (AMR) AF: 0.775 AC: 11855 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.728 AC: 2522 AN: 3466

East Asian (EAS) AF: 0.569 AC: 2926 AN: 5146

South Asian (SAS) AF: 0.735 AC: 3545 AN: 4820

European-Finnish (FIN) AF: 0.724 AC: 7670 AN: 10592

Middle Eastern (MID) AF: 0.724 AC: 213 AN: 294

European-Non Finnish (NFE) AF: 0.742 AC: 50480 AN: 67994

Other (OTH) AF: 0.766 AC: 1618 AN: 2112

Alfa AF: 0.764 Hom.: 130704

Bravo AF: 0.803

Asia WGS AF: 0.729 AC: 2537 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hyper-IgM syndrome type 3 Benign:4

Jul 28, 2017

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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.

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Benign:3

Jul 07, 2020

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency

Jan 24, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 95% of patients studied by a panel of primary immunodeficiencies. Number of patients: 90. Only high quality variants are reported.

not provided Benign:3

Apr 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

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

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 20137882, 18287517, 20127135, 21091218, 17344890, 20473910, 23669336, 18097708, 20634952, 24828072, 15731360, 27745838, 29780830, 31373353, 31642196, 23954880)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	12
DANN	Benign	0.75
PhyloP100		-0.19
PromoterAI		0.17	Neutral
Mutation Taster		=300/0	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: rs1883832; hg19: chr20-44746982; COSMIC: COSV64847693; COSMIC: COSV64847693;