rs11086998

Variant names:

• chr20-46128885-C-A
• rs11086998
• NM_001250.6:c.679C>A

Your query was ambiguous. Multiple possible variants found:

• chr20-46128885-C-A
• chr20-46128885-C-G
• chr20-46128885-C-T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001250.6(CD40):​c.679C>A​(p.Pro227Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P227A) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CD40 NM_001250.6 missense
• Clinical Significance: Not reported in ClinVar
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06670436).

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>A	p.Pro227Thr	missense	Exon 9 of 9	NP_001241.1
	CD40	NM_001322421.2		c.691C>A	p.Pro231Thr	missense	Exon 9 of 9	NP_001309350.1
	CD40	NM_001424339.1		c.535C>A	p.Pro179Thr	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>A	p.Pro227Thr	missense	Exon 9 of 9	ENSP00000361359.3
	CD40	ENST00000372276.7	TSL:1	c.*5C>A		3_prime_UTR	Exon 8 of 8	ENSP00000361350.3
	CD40	ENST00000466205.5	TSL:1	n.*102C>A		non_coding_transcript_exon	Exon 8 of 8	ENSP00000434825.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	0.0020
DANN	Benign	0.48
DEOGEN2	Benign	0.20	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.071	N
LIST_S2	Benign	0.40	T
M_CAP	Benign	0.051	D
MetaRNN	Benign	0.067	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		-1.6
PrimateAI	Benign	0.21	T
PROVEAN	Benign	0.14	N
REVEL	Benign	0.081
Sift	Benign	0.39	T
Sift4G	Benign	0.44	T
Polyphen		0.0060	B
Vest4		0.023
MutPred		0.19		Gain of MoRF binding (P = 0.1047)
MVP		0.58
MPC		0.52
ClinPred		0.22	T
GERP RS		-4.9
Varity_R		0.031
gMVP		0.19
Mutation Taster		=98/2	polymorphism

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;