chr20-46118465-C-T

Variant names:

• chr20-46118465-C-T
• rs11569302
• NM_001250.6:c.51+71C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001250.6(CD40):​c.51+71C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00892 in 918,078 control chromosomes in the GnomAD database, including 343 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.030 (193 hom., cov: 32)
  • Exomes 𝑓: 0.0051 (150 hom.)
• Consequence: CD40 NM_001250.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.751
• Publications: 3 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: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 20-46118465-C-T is Benign according to our data. Variant chr20-46118465-C-T is described in ClinVar as Benign. ClinVar VariationId is 1287702.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0992 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.51+71C>T		intron	N/A	NP_001241.1	P25942-1
	CD40	NM_001322421.2		c.51+71C>T		intron	N/A	NP_001309350.1
	CD40	NM_001302753.2		c.51+71C>T		intron	N/A	NP_001289682.1	A0A8Q3SI60

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CD40	ENST00000372285.8	TSL:1 MANE Select	c.51+71C>T		intron	N/A	ENSP00000361359.3	P25942-1
	CD40	ENST00000372276.7	TSL:1	c.51+71C>T		intron	N/A	ENSP00000361350.3	P25942-2
	CD40	ENST00000466205.5	TSL:1	n.45+71C>T		intron	N/A	ENSP00000434825.1	H0YE23

Frequencies

GnomAD3 genomes AF: 0.0304 AC: 4237 AN: 139476 Hom.: 194 Cov.: 32

Gnomad AFR AF: 0.102

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0115

Gnomad ASJ AF: 0.00183

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00449

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0132

Gnomad NFE AF: 0.000470

Gnomad OTH AF: 0.0213

GnomAD4 exome AF: 0.00508 AC: 3951 AN: 778474 Hom.: 150 AF XY: 0.00450 AC XY: 1823 AN XY: 405098

African (AFR) AF: 0.143 AC: 2790 AN: 19512

American (AMR) AF: 0.00840 AC: 316 AN: 37622

Ashkenazi Jewish (ASJ) AF: 0.00284 AC: 44 AN: 15512

East Asian (EAS) AF: 0.00 AC: 0 AN: 16174

South Asian (SAS) AF: 0.00175 AC: 129 AN: 73586

European-Finnish (FIN) AF: 0.0000272 AC: 1 AN: 36736

Middle Eastern (MID) AF: 0.00974 AC: 36 AN: 3696

European-Non Finnish (NFE) AF: 0.000522 AC: 284 AN: 544338

Other (OTH) AF: 0.0112 AC: 351 AN: 31298

GnomAD4 genome AF: 0.0304 AC: 4237 AN: 139604 Hom.: 193 Cov.: 32 AF XY: 0.0299 AC XY: 2024 AN XY: 67650

African (AFR) AF: 0.102 AC: 3976 AN: 39042

American (AMR) AF: 0.0114 AC: 162 AN: 14196

Ashkenazi Jewish (ASJ) AF: 0.00183 AC: 6 AN: 3280

East Asian (EAS) AF: 0.00 AC: 0 AN: 3858

South Asian (SAS) AF: 0.00448 AC: 17 AN: 3798

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8418

Middle Eastern (MID) AF: 0.0143 AC: 4 AN: 280

European-Non Finnish (NFE) AF: 0.000469 AC: 30 AN: 63898

Other (OTH) AF: 0.0211 AC: 42 AN: 1988

Alfa AF: 0.0236 Hom.: 17

Bravo AF: 0.0318

Asia WGS AF: 0.00635 AC: 22 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	5.9
DANN	Benign	0.81
PhyloP100		-0.75
PromoterAI		-0.033	Neutral
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: rs11569302; hg19: chr20-44747104;