20-46118099-C-T

Variant names:

• chr20-46118099-C-T
• rs752118
• NM_001250.6:c.-245C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001250.6(CD40):​c.-245C>T variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.192 in 152,264 control chromosomes in the GnomAD database, including 3,327 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.19 (3327 hom., cov: 33)
• Consequence: CD40 NM_001250.6 upstream_gene
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.128
• Publications: 19 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 20-46118099-C-T is Benign according to our data. Variant chr20-46118099-C-T is described in ClinVar as Benign. ClinVar VariationId is 1286483.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.3 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.-245C>T		upstream_gene	N/A	NP_001241.1
	CD40	NM_001322421.2		c.-245C>T		upstream_gene	N/A	NP_001309350.1
	CD40	NM_001302753.2		c.-245C>T		upstream_gene	N/A	NP_001289682.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CD40	ENST00000372285.8	TSL:1 MANE Select	c.-245C>T		upstream_gene	N/A	ENSP00000361359.3
	CD40	ENST00000372276.7	TSL:1	c.-245C>T		upstream_gene	N/A	ENSP00000361350.3
	CD40	ENST00000466205.5	TSL:1	n.-251C>T		upstream_gene	N/A	ENSP00000434825.1

Frequencies

GnomAD3 genomes AF: 0.192 AC: 29160 AN: 152144 Hom.: 3324 Cov.: 33

Gnomad AFR AF: 0.0676

Gnomad AMI AF: 0.354

Gnomad AMR AF: 0.162

Gnomad ASJ AF: 0.300

Gnomad EAS AF: 0.280

Gnomad SAS AF: 0.312

Gnomad FIN AF: 0.247

Gnomad MID AF: 0.263

Gnomad NFE AF: 0.242

Gnomad OTH AF: 0.191

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

GnomAD4 genome AF: 0.192 AC: 29166 AN: 152264 Hom.: 3327 Cov.: 33 AF XY: 0.194 AC XY: 14410 AN XY: 74456

African (AFR) AF: 0.0677 AC: 2812 AN: 41554

American (AMR) AF: 0.162 AC: 2482 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.300 AC: 1041 AN: 3472

East Asian (EAS) AF: 0.281 AC: 1454 AN: 5182

South Asian (SAS) AF: 0.313 AC: 1509 AN: 4822

European-Finnish (FIN) AF: 0.247 AC: 2624 AN: 10602

Middle Eastern (MID) AF: 0.259 AC: 76 AN: 294

European-Non Finnish (NFE) AF: 0.242 AC: 16441 AN: 68010

Other (OTH) AF: 0.191 AC: 404 AN: 2114

Alfa AF: 0.210 Hom.: 621

Bravo AF: 0.180

Asia WGS AF: 0.236 AC: 824 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	6.7
DANN	Benign	0.82
PhyloP100		-0.13
PromoterAI		0.071	Neutral
Mutation Taster		=100/0	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs752118; hg19: chr20-44746738;