chr6-32029631-C-T
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 1P and 2B. PP2BP4_Moderate
The NM_001002029.4(C4B):c.3742C>T(p.Arg1248Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.0000067 ( 0 hom., cov: 30)
Exomes 𝑓: 0.000014 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
C4B
NM_001002029.4 missense
NM_001002029.4 missense
Scores
4
13
Clinical Significance
Conservation
PhyloP100: 1.56
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 Likely_benign. Variant got -1 ACMG points.
PP2
?
Missense variant where missense usually causes diseases, C4B
BP4
?
Computational evidence support a benign effect (MetaRNN=0.18448853).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
C4B | NM_001002029.4 | c.3742C>T | p.Arg1248Cys | missense_variant | 29/41 | ENST00000435363.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
C4B | ENST00000435363.7 | c.3742C>T | p.Arg1248Cys | missense_variant | 29/41 | 1 | NM_001002029.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00 AC: 1AN: 150188Hom.: 0 Cov.: 30 FAILED QC
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GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000137 AC: 20AN: 1457936Hom.: 0 Cov.: 86 AF XY: 0.0000110 AC XY: 8AN XY: 725232
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GnomAD4 genome ? Data not reliable, filtered out with message: AS_VQSR AF: 0.00000666 AC: 1AN: 150188Hom.: 0 Cov.: 30 AF XY: 0.0000137 AC XY: 1AN XY: 73166
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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 | Jun 28, 2023 | The c.3742C>T (p.R1248C) alteration is located in exon 29 (coding exon 29) of the C4B gene. This alteration results from a C to T substitution at nucleotide position 3742, causing the arginine (R) at amino acid position 1248 to be replaced by a cysteine (C). 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
Benign
T
BayesDel_noAF
Benign
Cadd
Uncertain
Dann
Uncertain
DEOGEN2
Benign
T;T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
N
M_CAP
Benign
T
MetaRNN
Benign
T;T
MetaSVM
Benign
T
MutationAssessor
Uncertain
M;.
MutationTaster
Benign
N;N
PROVEAN
Benign
N;N
REVEL
Benign
Sift
Uncertain
D;D
Sift4G
Uncertain
D;D
Polyphen
0.99
.;D
Vest4
MutPred
Gain of catalytic residue at P1247 (P = 0.0123);Gain of catalytic residue at P1247 (P = 0.0123);
MVP
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at