chr20-46121857-A-G

Variant names:

• chr20-46121857-A-G
• rs2145590363
• NM_001250.6:c.89A>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM1 PM2 BP4

The NM_001250.6(CD40):​c.89A>G​(p.Gln30Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CD40 NM_001250.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.16
• Publications: 0 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: Uncertain_significance. The variant received 3 ACMG points.

• PM1: In a topological_domain Extracellular (size 172) in uniprot entity TNR5_HUMAN there are 4 pathogenic changes around while only 1 benign (80%) in NM_001250.6
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.39399317).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CD40	NM_001250.6	c.89A>G	p.Gln30Arg	missense_variant	Exon 2 of 9	ENST00000372285.8	NP_001241.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CD40	ENST00000372285.8	c.89A>G	p.Gln30Arg	missense_variant	Exon 2 of 9	1	NM_001250.6	ENSP00000361359.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Oct 08, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals affected with CD40-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces glutamine with arginine at codon 30 of the CD40 protein (p.Gln30Arg). The glutamine residue is highly conserved and there is a small physicochemical difference between glutamine and arginine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Uncertain	0.043	T
BayesDel_noAF	Benign	-0.18
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.39	T;.;.
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Benign	0.66	D
LIST_S2	Benign	0.77	T;T;T
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.39	T;T;T
MetaSVM	Uncertain	0.16	D
MutationAssessor	Uncertain	2.7	M;.;M
PhyloP100		4.2
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-2.2	N;.;N
REVEL	Uncertain	0.42
Sift	Uncertain	0.0070	D;.;D
Sift4G	Uncertain	0.0050	D;D;D
Polyphen		1.0	D;.;D
Vest4		0.33
MutPred		0.47		Loss of ubiquitination at K29 (P = 0.0795);Loss of ubiquitination at K29 (P = 0.0795);Loss of ubiquitination at K29 (P = 0.0795);
MVP		0.97
MPC		1.4
ClinPred		0.91	D
GERP RS		3.8
Varity_R		0.36
gMVP		0.88
Mutation Taster		=70/30	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs2145590363; hg19: chr20-44750496;