chr6-32027043-G-T
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP2PP3_Moderate
The NM_001002029.4(C4B):c.2513G>T(p.Arg838Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R838H) has been classified as Uncertain significance.
Frequency
Genomes: not found (cov: 18)
Consequence
C4B
NM_001002029.4 missense
NM_001002029.4 missense
Scores
4
7
6
Clinical Significance
Conservation
PhyloP100: 4.49
Genes affected
C4B (HGNC:1324): (complement C4B (Chido/Rodgers blood group)) This gene encodes the basic form of complement factor 4, and together with the C4A gene, is part of the classical activation pathway. The protein is expressed as a single chain precursor which is proteolytically cleaved into a trimer of alpha, beta, and gamma chains prior to secretion. The trimer provides a surface for interaction between the antigen-antibody complex and other complement components. The alpha chain may be cleaved to release C4 anaphylatoxin, a mediator of local inflammation. Deficiency of this protein is associated with systemic lupus erythematosus. This gene localizes to the major histocompatibility complex (MHC) class III region on chromosome 6. Varying haplotypes of this gene cluster exist, such that individuals may have 1, 2, or 3 copies of this gene. In addition, this gene exists as a long form and a short form due to the presence or absence of a 6.4 kb endogenous HERV-K retrovirus in intron 9. [provided by RefSeq, May 2020]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 5 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP2
?
Missense variant where missense usually causes diseases, C4B
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.861
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
C4B | NM_001002029.4 | c.2513G>T | p.Arg838Leu | missense_variant | 20/41 | ENST00000435363.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
C4B | ENST00000435363.7 | c.2513G>T | p.Arg838Leu | missense_variant | 20/41 | 1 | NM_001002029.4 | P1 | |
C4B | ENST00000425700.3 | c.2513G>T | p.Arg838Leu | missense_variant | 20/40 | 1 | |||
C4B | ENST00000647698.1 | c.1220G>T | p.Arg407Leu | missense_variant | 10/31 | ||||
C4B | ENST00000648821.1 | n.947G>T | non_coding_transcript_exon_variant | 8/27 |
Frequencies
GnomAD3 genomes ? Cov.: 18
GnomAD3 genomes
?
Cov.:
18
GnomAD4 exome Cov.: 32
GnomAD4 exome
Cov.:
32
GnomAD4 genome ? Cov.: 18
GnomAD4 genome
?
Cov.:
18
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 20, 2023 | The c.2513G>T (p.R838L) alteration is located in exon 20 (coding exon 20) of the C4B gene. This alteration results from a G to T substitution at nucleotide position 2513, causing the arginine (R) at amino acid position 838 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
T
BayesDel_noAF
Benign
Cadd
Pathogenic
Dann
Uncertain
DEOGEN2
Benign
T;T
Eigen
Pathogenic
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
M_CAP
Benign
D
MetaRNN
Pathogenic
D;D
MetaSVM
Benign
T
MutationAssessor
Uncertain
M;.
MutationTaster
Benign
D;D
PROVEAN
Pathogenic
D;D
REVEL
Uncertain
Sift
Uncertain
D;D
Sift4G
Pathogenic
D;D
Polyphen
1.0
.;D
Vest4
MutPred
Loss of MoRF binding (P = 0.0162);Loss of MoRF binding (P = 0.0162);
MVP
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at