NM_001250.6:c.498-168G>T

Variant names:

• chr20-46126472-G-T
• rs3746821
• NM_001250.6:c.498-168G>T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001250.6(CD40):​c.498-168G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.126 in 152,190 control chromosomes in the GnomAD database, including 1,504 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency: Genomes: 𝑓 0.13 (1504 hom., cov: 32)
• Consequence: CD40 NM_001250.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -3.13

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 20-46126472-G-T is Benign according to our data. Variant chr20-46126472-G-T is described in ClinVar as [Benign]. Clinvar id is 1225541.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.405 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CD40	NM_001250.6	c.498-168G>T		intron_variant	Intron 5 of 8	ENST00000372285.8	NP_001241.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CD40	ENST00000372285.8	c.498-168G>T		intron_variant	Intron 5 of 8	1	NM_001250.6	ENSP00000361359.3

Frequencies

GnomAD3 genomes AF: 0.126 AC: 19210 AN: 152072 Hom.: 1507 Cov.: 32

Gnomad AFR AF: 0.110

Gnomad AMI AF: 0.167

Gnomad AMR AF: 0.120

Gnomad ASJ AF: 0.0674

Gnomad EAS AF: 0.420

Gnomad SAS AF: 0.175

Gnomad FIN AF: 0.126

Gnomad MID AF: 0.114

Gnomad NFE AF: 0.115

Gnomad OTH AF: 0.123

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

GnomAD4 genome AF: 0.126 AC: 19214 AN: 152190 Hom.: 1504 Cov.: 32 AF XY: 0.129 AC XY: 9626 AN XY: 74408

Gnomad4 AFR AF: 0.110

Gnomad4 AMR AF: 0.120

Gnomad4 ASJ AF: 0.0674

Gnomad4 EAS AF: 0.420

Gnomad4 SAS AF: 0.175

Gnomad4 FIN AF: 0.126

Gnomad4 NFE AF: 0.115

Gnomad4 OTH AF: 0.122

Alfa AF: 0.102 Hom.: 530

Bravo AF: 0.125

Asia WGS AF: 0.232 AC: 806 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Sep 20, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 22446962) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.025
DANN	Benign	0.83

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs3746821; hg19: chr20-44755111; COSMIC: COSV64848264;