NM_001250.6:c.679C>G

Variant names:

• chr20-46128885-C-G
• rs11086998
• NM_001250.6:c.679C>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.679C>G​(p.Pro227Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0104 in 1,614,024 control chromosomes in the GnomAD database, including 523 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Synonymous variant affecting the same amino acid position (i.e. P227P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.015 (112 hom., cov: 32)
  • Exomes 𝑓: 0.0099 (411 hom.)
• Consequence: CD40 NM_001250.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.61
• Publications: 25 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 (MetaRNN=0.0016620457).
• BP6: Variant 20-46128885-C-G is Benign according to our data. Variant chr20-46128885-C-G is described in ClinVar as Benign. ClinVar VariationId is 338576.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0964 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.679C>G	p.Pro227Ala	missense	Exon 9 of 9	NP_001241.1
	CD40	NM_001322421.2		c.691C>G	p.Pro231Ala	missense	Exon 9 of 9	NP_001309350.1
	CD40	NM_001424339.1		c.535C>G	p.Pro179Ala	missense	Exon 7 of 7	NP_001411268.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CD40	ENST00000372285.8	TSL:1 MANE Select	c.679C>G	p.Pro227Ala	missense	Exon 9 of 9	ENSP00000361359.3
	CD40	ENST00000372276.7	TSL:1	c.*5C>G		3_prime_UTR	Exon 8 of 8	ENSP00000361350.3
	CD40	ENST00000466205.5	TSL:1	n.*102C>G		non_coding_transcript_exon	Exon 8 of 8	ENSP00000434825.1

Frequencies

GnomAD3 genomes AF: 0.0152 AC: 2307 AN: 152140 Hom.: 112 Cov.: 32

Gnomad AFR AF: 0.00413

Gnomad AMI AF: 0.0329

Gnomad AMR AF: 0.100

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00231

Gnomad SAS AF: 0.00580

Gnomad FIN AF: 0.00113

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00715

Gnomad OTH AF: 0.0154

GnomAD2 exomes AF: 0.0218 AC: 5462 AN: 250810 AF XY: 0.0176

Gnomad AFR exome AF: 0.00351

Gnomad AMR exome AF: 0.123

Gnomad ASJ exome AF: 0.000497

Gnomad EAS exome AF: 0.00266

Gnomad FIN exome AF: 0.00171

Gnomad NFE exome AF: 0.00693

Gnomad OTH exome AF: 0.0199

GnomAD4 exome AF: 0.00993 AC: 14513 AN: 1461766 Hom.: 411 Cov.: 32 AF XY: 0.00937 AC XY: 6811 AN XY: 727178

African (AFR) AF: 0.00260 AC: 87 AN: 33480

American (AMR) AF: 0.121 AC: 5400 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.000497 AC: 13 AN: 26136

East Asian (EAS) AF: 0.00242 AC: 96 AN: 39700

South Asian (SAS) AF: 0.00443 AC: 382 AN: 86258

European-Finnish (FIN) AF: 0.00187 AC: 100 AN: 53392

Middle Eastern (MID) AF: 0.00260 AC: 15 AN: 5768

European-Non Finnish (NFE) AF: 0.00702 AC: 7804 AN: 1111930

Other (OTH) AF: 0.0102 AC: 616 AN: 60384

GnomAD4 genome AF: 0.0152 AC: 2311 AN: 152258 Hom.: 112 Cov.: 32 AF XY: 0.0167 AC XY: 1242 AN XY: 74444

African (AFR) AF: 0.00412 AC: 171 AN: 41544

American (AMR) AF: 0.101 AC: 1539 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00232 AC: 12 AN: 5178

South Asian (SAS) AF: 0.00581 AC: 28 AN: 4822

European-Finnish (FIN) AF: 0.00113 AC: 12 AN: 10624

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00715 AC: 486 AN: 68008

Other (OTH) AF: 0.0152 AC: 32 AN: 2106

Alfa AF: 0.00772 Hom.: 5

Bravo AF: 0.0216

TwinsUK AF: 0.00701 AC: 26

ALSPAC AF: 0.00727 AC: 28

ESP6500AA AF: 0.00386 AC: 17

ESP6500EA AF: 0.00802 AC: 69

ExAC AF: 0.0170 AC: 2068

Asia WGS AF: 0.00924 AC: 32 AN: 3478

EpiCase AF: 0.00622

EpiControl AF: 0.00688

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Hyper-IgM syndrome type 3 (2)
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	0.0010
DANN	Benign	0.42
DEOGEN2	Benign	0.20	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.053	N
LIST_S2	Benign	0.39	T
MetaRNN	Benign	0.0017	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		-1.6
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-0.070	N
REVEL	Benign	0.077
Sift	Benign	0.51	T
Sift4G	Benign	0.58	T
Polyphen		0.0030	B
Vest4		0.020
MPC		0.45
ClinPred		0.0035	T
GERP RS		-4.9
Varity_R		0.024
gMVP		0.16
Mutation Taster		=99/1	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: rs11086998; hg19: chr20-44757524;