20-46120612-T-C

Variant names:

• chr20-46120612-T-C
• rs4239702
• NM_001250.6:c.52-1208T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001250.6(CD40):​c.52-1208T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.745 in 152,240 control chromosomes in the GnomAD database, including 42,597 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.75 (42597 hom., cov: 34)
• Consequence: CD40 NM_001250.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.233
• Publications: 67 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.83 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001250.6. 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
	CD40	NM_001250.6	MANE Select	c.52-1208T>C		intron	N/A	NP_001241.1	P25942-1
	CD40	NM_001322421.2		c.52-1208T>C		intron	N/A	NP_001309350.1
	CD40	NM_001302753.2		c.52-1208T>C		intron	N/A	NP_001289682.1	A0A8Q3SI60

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CD40	ENST00000372285.8	TSL:1 MANE Select	c.52-1208T>C		intron	N/A	ENSP00000361359.3	P25942-1
	CD40	ENST00000372276.7	TSL:1	c.52-1208T>C		intron	N/A	ENSP00000361350.3	P25942-2
	CD40	ENST00000466205.5	TSL:1	n.46-1208T>C		intron	N/A	ENSP00000434825.1	H0YE23

Frequencies

GnomAD3 genomes AF: 0.745 AC: 113331 AN: 152122 Hom.: 42551 Cov.: 34

Gnomad AFR AF: 0.838

Gnomad AMI AF: 0.751

Gnomad AMR AF: 0.748

Gnomad ASJ AF: 0.649

Gnomad EAS AF: 0.568

Gnomad SAS AF: 0.730

Gnomad FIN AF: 0.698

Gnomad MID AF: 0.709

Gnomad NFE AF: 0.716

Gnomad OTH AF: 0.722

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.745 AC: 113434 AN: 152240 Hom.: 42597 Cov.: 34 AF XY: 0.740 AC XY: 55054 AN XY: 74430

African (AFR) AF: 0.837 AC: 34769 AN: 41522

American (AMR) AF: 0.749 AC: 11454 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.649 AC: 2252 AN: 3472

East Asian (EAS) AF: 0.568 AC: 2941 AN: 5178

South Asian (SAS) AF: 0.729 AC: 3521 AN: 4828

European-Finnish (FIN) AF: 0.698 AC: 7393 AN: 10594

Middle Eastern (MID) AF: 0.707 AC: 208 AN: 294

European-Non Finnish (NFE) AF: 0.716 AC: 48679 AN: 68022

Other (OTH) AF: 0.724 AC: 1532 AN: 2116

Alfa AF: 0.727 Hom.: 77330

Bravo AF: 0.753

Asia WGS AF: 0.712 AC: 2475 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	8.7
DANN	Benign	0.88
PhyloP100		0.23
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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs4239702;

hg19: chr20-44749251;