NM_001250.6:c.675+216A>G

Variant names:

• chr20-46128574-A-G
• rs3765457
• NM_001250.6:c.675+216A>G

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.675+216A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.131 in 711,102 control chromosomes in the GnomAD database, including 6,865 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (1138 hom., cov: 30)
  • Exomes 𝑓: 0.14 (5727 hom.)
• Consequence: CD40 NM_001250.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.24
• Publications: 23 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.014).
• BP6: Variant 20-46128574-A-G is Benign according to our data. Variant chr20-46128574-A-G is described in ClinVar as Benign. ClinVar VariationId is 1236220.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.157 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CD40	NM_001250.6	MANE Select	c.675+216A>G		intron	N/A	NP_001241.1
	CD40	NM_001322421.2		c.687+216A>G		intron	N/A	NP_001309350.1
	CD40	NM_001302753.2		c.*1+216A>G		intron	N/A	NP_001289682.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CD40	ENST00000372285.8	TSL:1 MANE Select	c.675+216A>G		intron	N/A	ENSP00000361359.3
	CD40	ENST00000372276.7	TSL:1	c.*1+216A>G		intron	N/A	ENSP00000361350.3
	CD40	ENST00000466205.5	TSL:1	n.*98+216A>G		intron	N/A	ENSP00000434825.1

Frequencies

GnomAD3 genomes AF: 0.114 AC: 17303 AN: 151844 Hom.: 1137 Cov.: 30

Gnomad AFR AF: 0.0524

Gnomad AMI AF: 0.0780

Gnomad AMR AF: 0.0763

Gnomad ASJ AF: 0.162

Gnomad EAS AF: 0.0313

Gnomad SAS AF: 0.119

Gnomad FIN AF: 0.140

Gnomad MID AF: 0.0981

Gnomad NFE AF: 0.160

Gnomad OTH AF: 0.121

GnomAD2 exomes AF: 0.118 AC: 15829 AN: 134174 AF XY: 0.123

Gnomad AFR exome AF: 0.0408

Gnomad AMR exome AF: 0.0600

Gnomad ASJ exome AF: 0.154

Gnomad EAS exome AF: 0.0297

Gnomad FIN exome AF: 0.140

Gnomad NFE exome AF: 0.157

Gnomad OTH exome AF: 0.129

GnomAD4 exome AF: 0.136 AC: 75804 AN: 559142 Hom.: 5727 Cov.: 5 AF XY: 0.136 AC XY: 41224 AN XY: 302100

African (AFR) AF: 0.0496 AC: 770 AN: 15530

American (AMR) AF: 0.0646 AC: 2093 AN: 32376

Ashkenazi Jewish (ASJ) AF: 0.152 AC: 2945 AN: 19378

East Asian (EAS) AF: 0.0364 AC: 1169 AN: 32134

South Asian (SAS) AF: 0.133 AC: 8137 AN: 61078

European-Finnish (FIN) AF: 0.144 AC: 5055 AN: 35070

Middle Eastern (MID) AF: 0.0924 AC: 373 AN: 4038

European-Non Finnish (NFE) AF: 0.156 AC: 51128 AN: 328776

Other (OTH) AF: 0.134 AC: 4134 AN: 30762

GnomAD4 genome AF: 0.114 AC: 17307 AN: 151960 Hom.: 1138 Cov.: 30 AF XY: 0.110 AC XY: 8206 AN XY: 74284

African (AFR) AF: 0.0524 AC: 2173 AN: 41456

American (AMR) AF: 0.0762 AC: 1163 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.162 AC: 561 AN: 3468

East Asian (EAS) AF: 0.0312 AC: 161 AN: 5164

South Asian (SAS) AF: 0.119 AC: 574 AN: 4818

European-Finnish (FIN) AF: 0.140 AC: 1478 AN: 10542

Middle Eastern (MID) AF: 0.102 AC: 30 AN: 294

European-Non Finnish (NFE) AF: 0.160 AC: 10845 AN: 67924

Other (OTH) AF: 0.119 AC: 251 AN: 2112

Alfa AF: 0.138 Hom.: 1978

Bravo AF: 0.106

Asia WGS AF: 0.0810 AC: 281 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

Oct 24, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.35
DANN	Benign	0.67
PhyloP100		-2.2
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3765457; hg19: chr20-44757213;