20-46129175-C-T

Variant names:

• chr20-46129175-C-T
• rs11569343
• ENST00000620709.4:n.*516C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The ENST00000620709.4(CD40):​n.*516C>T variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000123 in 810,430 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 32)
  • Exomes 𝑓: 0.0000012 (0 hom.)
• Consequence: CD40 ENST00000620709.4 non_coding_transcript_exon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.169
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000620709.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CD40	NM_001250.6	MANE Select	c.*135C>T		3_prime_UTR	Exon 9 of 9	NP_001241.1
	CD40	NR_126502.2		n.1002C>T		non_coding_transcript_exon	Exon 7 of 7
	CD40	NR_136327.2		n.905C>T		non_coding_transcript_exon	Exon 8 of 8

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CD40	ENST00000620709.4	TSL:1	n.*516C>T		non_coding_transcript_exon	Exon 7 of 7	ENSP00000484074.1
	CD40	ENST00000372285.8	TSL:1 MANE Select	c.*135C>T		3_prime_UTR	Exon 9 of 9	ENSP00000361359.3
	CD40	ENST00000372276.7	TSL:1	c.*295C>T		3_prime_UTR	Exon 8 of 8	ENSP00000361350.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000123 AC: 1 AN: 810430 Hom.: 0 Cov.: 11 AF XY: 0.00000236 AC XY: 1 AN XY: 423190

African (AFR) AF: 0.00 AC: 0 AN: 20980

American (AMR) AF: 0.00 AC: 0 AN: 36474

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21618

East Asian (EAS) AF: 0.0000294 AC: 1 AN: 34066

South Asian (SAS) AF: 0.00 AC: 0 AN: 69402

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 36364

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4110

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 548166

Other (OTH) AF: 0.00 AC: 0 AN: 39250

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	2.9
DANN	Benign	0.62
PhyloP100		-0.17

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: rs11569343; hg19: chr20-44757814;