rs148594123
Variant summary
Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBS1BS2
The NM_000074.3(CD40LG):c.655G>A(p.Gly219Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.015 in 1,209,678 control chromosomes in the GnomAD database, including 122 homozygotes. There are 5,855 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Consequence
NM_000074.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CD40LG | NM_000074.3 | c.655G>A | p.Gly219Arg | missense_variant | 5/5 | ENST00000370629.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CD40LG | ENST00000370629.7 | c.655G>A | p.Gly219Arg | missense_variant | 5/5 | 1 | NM_000074.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0100 AC: 1120AN: 111961Hom.: 6 Cov.: 23 AF XY: 0.00984 AC XY: 336AN XY: 34159
GnomAD3 exomes AF: 0.0111 AC: 2024AN: 182591Hom.: 16 AF XY: 0.0109 AC XY: 732AN XY: 67227
GnomAD4 exome AF: 0.0156 AC: 17075AN: 1097663Hom.: 116 Cov.: 31 AF XY: 0.0152 AC XY: 5519AN XY: 363053
GnomAD4 genome ? AF: 0.0100 AC: 1122AN: 112015Hom.: 6 Cov.: 23 AF XY: 0.00982 AC XY: 336AN XY: 34223
ClinVar
Submissions by phenotype
not specified Benign:2
Benign, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jul 20, 2016 | - - |
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 08, 2016 | Variant summary: The CD40LG c.655G>A variant affects a non-conserved nucleotide, resulting in amino acid change from Gly to Arg. 3/5 in-silico tools predict this variant to be damaging. In vitro functional studies suggest that G219R has decreased ligand binding and decreased capacity to activate B cells. However, the single expression of G219R protein has no or only minor effects in vivo as shown by an asymptomatic carrier of G219R who has normal values of serum IgA and IgM and normal B-cell subpopulations (Rigaud 2011). These functional studies suggest that this variant is a functional polymorphism.This variant was found in 992/88003 control chromosomes (at least 7 homozygotes and 388 hemizygotes) at a frequency of 0.0112723, which is about 7 times the maximal expected frequency of a pathogenic CD40LG allele (0.0015811) for HIGM1, suggesting this variant is benign. The variant has been reported in patients with hyper IgM syndrome, non-X-linked HIGM, X-linked variable immunodeficiency, and hypogammaglobulinemia, However, some of these patients had other probable disease causing mutations in cis (Gln232X; Lin 1996) or in another gene (XIAP G466X; Rigaud 2011), or unaffected compound heterozygous or hemizygous family members (lack of segregation with disease; Martinez-Martinez 2012 and Rigaud 2011), suggesting that this variant itself is not pathogenic in isolation. Taken together, this variant is not disease causing in isolation but may play a contributory role in certain backgrounds, and therefore is classified as benign. - |
Hyper-IgM syndrome type 1 Benign:2
Likely benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Oct 09, 2023 | - - |
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at