NM_001250.6:c.51+53G>A

Variant names:

• chr20-46118447-G-A
• rs745307
• NM_001250.6:c.51+53G>A

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+53G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.253 in 1,443,336 control chromosomes in the GnomAD database, including 46,725 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.18 (2950 hom., cov: 32)
  • Exomes 𝑓: 0.26 (43775 hom.)
• Consequence: CD40 NM_001250.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.382
• Publications: 43 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=-0.9).
• BP6: Variant 20-46118447-G-A is Benign according to our data. Variant chr20-46118447-G-A is described in ClinVar as Benign. ClinVar VariationId is 1245520.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.255 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+53G>A		intron	N/A	NP_001241.1	P25942-1
	CD40	NM_001322421.2		c.51+53G>A		intron	N/A	NP_001309350.1
	CD40	NM_001302753.2		c.51+53G>A		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+53G>A		intron	N/A	ENSP00000361359.3	P25942-1
	CD40	ENST00000372276.7	TSL:1	c.51+53G>A		intron	N/A	ENSP00000361350.3	P25942-2
	CD40	ENST00000466205.5	TSL:1	n.45+53G>A		intron	N/A	ENSP00000434825.1	H0YE23

Frequencies

GnomAD3 genomes AF: 0.180 AC: 26856 AN: 149476 Hom.: 2949 Cov.: 32

Gnomad AFR AF: 0.0653

Gnomad AMI AF: 0.237

Gnomad AMR AF: 0.126

Gnomad ASJ AF: 0.186

Gnomad EAS AF: 0.0337

Gnomad SAS AF: 0.183

Gnomad FIN AF: 0.259

Gnomad MID AF: 0.178

Gnomad NFE AF: 0.258

Gnomad OTH AF: 0.187

GnomAD4 exome AF: 0.262 AC: 338338 AN: 1293722 Hom.: 43775 AF XY: 0.261 AC XY: 168537 AN XY: 645632

African (AFR) AF: 0.0690 AC: 1923 AN: 27850

American (AMR) AF: 0.109 AC: 4392 AN: 40130

Ashkenazi Jewish (ASJ) AF: 0.221 AC: 4717 AN: 21368

East Asian (EAS) AF: 0.0610 AC: 1421 AN: 23304

South Asian (SAS) AF: 0.189 AC: 15857 AN: 84046

European-Finnish (FIN) AF: 0.308 AC: 13293 AN: 43202

Middle Eastern (MID) AF: 0.203 AC: 1002 AN: 4928

European-Non Finnish (NFE) AF: 0.284 AC: 283146 AN: 998184

Other (OTH) AF: 0.248 AC: 12587 AN: 50710

GnomAD4 genome AF: 0.179 AC: 26853 AN: 149614 Hom.: 2950 Cov.: 32 AF XY: 0.177 AC XY: 12914 AN XY: 73116

African (AFR) AF: 0.0652 AC: 2678 AN: 41064

American (AMR) AF: 0.126 AC: 1898 AN: 15076

Ashkenazi Jewish (ASJ) AF: 0.186 AC: 639 AN: 3428

East Asian (EAS) AF: 0.0336 AC: 160 AN: 4768

South Asian (SAS) AF: 0.184 AC: 837 AN: 4558

European-Finnish (FIN) AF: 0.259 AC: 2626 AN: 10148

Middle Eastern (MID) AF: 0.182 AC: 53 AN: 292

European-Non Finnish (NFE) AF: 0.258 AC: 17365 AN: 67280

Other (OTH) AF: 0.183 AC: 384 AN: 2102

Alfa AF: 0.220 Hom.: 5123

Bravo AF: 0.163

Asia WGS AF: 0.100 AC: 349 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	11
DANN	Benign	0.72
PhyloP100		0.38
PromoterAI		-0.0042	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: rs745307; hg19: chr20-44747086; COSMIC: COSV64847751; COSMIC: COSV64847751;