NM_001250.6:c.51+1517T>C

Variant names:

• chr20-46119911-T-C
• rs11569309
• NM_001250.6:c.51+1517T>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.51+1517T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.138 in 152,098 control chromosomes in the GnomAD database, including 1,714 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 0.14 (1714 hom., cov: 32)
• Consequence: CD40 NM_001250.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.29
• Publications: 18 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.188 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CD40	NM_001250.6	c.51+1517T>C		intron_variant	Intron 1 of 8	ENST00000372285.8	NP_001241.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CD40	ENST00000372285.8	c.51+1517T>C		intron_variant	Intron 1 of 8	1	NM_001250.6	ENSP00000361359.3

Frequencies

GnomAD3 genomes AF: 0.138 AC: 20937 AN: 151980 Hom.: 1713 Cov.: 32

Gnomad AFR AF: 0.0558

Gnomad AMI AF: 0.163

Gnomad AMR AF: 0.101

Gnomad ASJ AF: 0.160

Gnomad EAS AF: 0.0310

Gnomad SAS AF: 0.112

Gnomad FIN AF: 0.223

Gnomad MID AF: 0.133

Gnomad NFE AF: 0.191

Gnomad OTH AF: 0.145

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

GnomAD4 genome AF: 0.138 AC: 20934 AN: 152098 Hom.: 1714 Cov.: 32 AF XY: 0.136 AC XY: 10136 AN XY: 74338

African (AFR) AF: 0.0557 AC: 2311 AN: 41516

American (AMR) AF: 0.101 AC: 1542 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.160 AC: 554 AN: 3468

East Asian (EAS) AF: 0.0311 AC: 161 AN: 5182

South Asian (SAS) AF: 0.112 AC: 537 AN: 4802

European-Finnish (FIN) AF: 0.223 AC: 2355 AN: 10566

Middle Eastern (MID) AF: 0.133 AC: 39 AN: 294

European-Non Finnish (NFE) AF: 0.191 AC: 12986 AN: 67972

Other (OTH) AF: 0.143 AC: 301 AN: 2110

Alfa AF: 0.168 Hom.: 454

Bravo AF: 0.126

Asia WGS AF: 0.0810 AC: 281 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	1.9
DANN	Benign	0.48
PhyloP100		-1.3
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: rs11569309; hg19: chr20-44748550;