20-46118274-CT-C

Position:

• chr20-46118274-CT-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The ENST00000695669.1(CD40):​n.5delT 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 0.00243 in 1,412,474 control chromosomes in the GnomAD database, including 82 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (36 hom., cov: 33)
  • Exomes 𝑓: 0.0013 (46 hom.)
• Consequence: CD40 ENST00000695669.1 non_coding_transcript_exon
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -4.55

Genes affected

CD40 (HGNC:):

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 -16 ACMG points.

• BP6: Variant 20-46118274-CT-C is Benign according to our data. Variant chr20-46118274-CT-C is described in ClinVar as [Likely_benign]. Clinvar id is 338565.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0115 (1756/152328) while in subpopulation AFR AF= 0.0404 (1681/41576). AF 95% confidence interval is 0.0388. There are 36 homozygotes in gnomad4. There are 818 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 36 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CD40	NM_001250.6	c.-69delT		upstream_gene_variant		ENST00000372285.8	NP_001241.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CD40	ENST00000372285.8	c.-69delT		upstream_gene_variant		1	NM_001250.6	ENSP00000361359.3

Frequencies

GnomAD3 genomes AF: 0.0115 AC: 1752 AN: 152210 Hom.: 36 Cov.: 33

Gnomad AFR AF: 0.0405

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00353

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00525

GnomAD4 exome AF: 0.00133 AC: 1681 AN: 1260146 Hom.: 46 Cov.: 18 AF XY: 0.00112 AC XY: 716 AN XY: 636822

Gnomad4 AFR exome AF: 0.0465

Gnomad4 AMR exome AF: 0.00187

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000855

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000101

Gnomad4 OTH exome AF: 0.00244

GnomAD4 genome AF: 0.0115 AC: 1756 AN: 152328 Hom.: 36 Cov.: 33 AF XY: 0.0110 AC XY: 818 AN XY: 74490

Gnomad4 AFR AF: 0.0404

Gnomad4 AMR AF: 0.00353

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.00520

Alfa AF: 0.000217 Hom.: 0

Bravo AF: 0.0136

Asia WGS AF: 0.00318 AC: 11 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Aug 17, 2016

Variant summary: The CD40 c.-69delT variant involves the alteration of a non-conserved nucleotide. One in silico tool predicts a benign outcome for this variant. This variant was found in 242/17514 control chromosomes, predominantly observed in the African subpopulation at a frequency of 0.0428 (239/5580). This frequency is about 271 times the estimated maximal expected allele frequency of a pathogenic CD40 variant (0.0001581), suggesting this is likely a benign polymorphism found primarily in the populations of origin. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as benign. -

Hyperimmunoglobulin M syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs11569300; hg19: chr20-44746913;