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GeneBe

6-31946402-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001710.6(CFB):c.94C>T(p.Arg32Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.109 in 1,612,892 control chromosomes in the GnomAD database, including 13,042 homozygotes. 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R32Q) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.17 ( 3028 hom., cov: 32)
Exomes 𝑓: 0.10 ( 10014 hom. )

Consequence

CFB
NM_001710.6 missense

Scores

2
14

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15

Conservation

PhyloP100: -0.787
Variant links:
Genes affected
CFB (HGNC:1037): (complement factor B) This gene encodes complement factor B, a component of the alternative pathway of complement activation. Factor B circulates in the blood as a single chain polypeptide. Upon activation of the alternative pathway, it is cleaved by complement factor D yielding the noncatalytic chain Ba and the catalytic subunit Bb. The active subunit Bb is a serine protease which associates with C3b to form the alternative pathway C3 convertase. Bb is involved in the proliferation of preactivated B lymphocytes, while Ba inhibits their proliferation. This gene localizes to the major histocompatibility complex (MHC) class III region on chromosome 6. This cluster includes several genes involved in regulation of the immune reaction. Polymorphisms in this gene are associated with a reduced risk of age-related macular degeneration. The polyadenylation site of this gene is 421 bp from the 5' end of the gene for complement component 2. [provided by RefSeq, Jul 2008]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.005584061).
BP6
Variant 6-31946402-C-T is Benign according to our data. Variant chr6-31946402-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 16076.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-31946402-C-T is described in Lovd as [Benign].
BA1
GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.325 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
CFBNM_001710.6 linkuse as main transcriptc.94C>T p.Arg32Trp missense_variant 2/18 ENST00000425368.7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
CFBENST00000425368.7 linkuse as main transcriptc.94C>T p.Arg32Trp missense_variant 2/181 NM_001710.6 P1P00751-1

Frequencies

GnomAD3 genomes
AF:
0.170
AC:
25908
AN:
152038
Hom.:
3019
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.329
Gnomad AMI
AF:
0.0899
Gnomad AMR
AF:
0.145
Gnomad ASJ
AF:
0.0897
Gnomad EAS
AF:
0.0612
Gnomad SAS
AF:
0.189
Gnomad FIN
AF:
0.167
Gnomad MID
AF:
0.196
Gnomad NFE
AF:
0.0923
Gnomad OTH
AF:
0.172
GnomAD3 exomes
AF:
0.124
AC:
30666
AN:
246544
Hom.:
2613
AF XY:
0.127
AC XY:
17133
AN XY:
134392
show subpopulations
Gnomad AFR exome
AF:
0.333
Gnomad AMR exome
AF:
0.0877
Gnomad ASJ exome
AF:
0.0913
Gnomad EAS exome
AF:
0.0605
Gnomad SAS exome
AF:
0.204
Gnomad FIN exome
AF:
0.156
Gnomad NFE exome
AF:
0.0929
Gnomad OTH exome
AF:
0.120
GnomAD4 exome
AF:
0.103
AC:
149734
AN:
1460736
Hom.:
10014
Cov.:
33
AF XY:
0.106
AC XY:
76903
AN XY:
726684
show subpopulations
Gnomad4 AFR exome
AF:
0.341
Gnomad4 AMR exome
AF:
0.0955
Gnomad4 ASJ exome
AF:
0.0939
Gnomad4 EAS exome
AF:
0.0695
Gnomad4 SAS exome
AF:
0.204
Gnomad4 FIN exome
AF:
0.152
Gnomad4 NFE exome
AF:
0.0860
Gnomad4 OTH exome
AF:
0.108
GnomAD4 genome
AF:
0.171
AC:
25960
AN:
152156
Hom.:
3028
Cov.:
32
AF XY:
0.174
AC XY:
12949
AN XY:
74388
show subpopulations
Gnomad4 AFR
AF:
0.329
Gnomad4 AMR
AF:
0.145
Gnomad4 ASJ
AF:
0.0897
Gnomad4 EAS
AF:
0.0612
Gnomad4 SAS
AF:
0.190
Gnomad4 FIN
AF:
0.167
Gnomad4 NFE
AF:
0.0923
Gnomad4 OTH
AF:
0.169
Alfa
AF:
0.102
Hom.:
1859
Bravo
AF:
0.175
TwinsUK
AF:
0.0823
AC:
305
ALSPAC
AF:
0.0921
AC:
355
ESP6500AA
AF:
0.319
AC:
964
ESP6500EA
AF:
0.0978
AC:
530
ExAC
AF:
0.131
AC:
15354
Asia WGS
AF:
0.125
AC:
437
AN:
3478
EpiCase
AF:
0.0966
EpiControl
AF:
0.0993

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:15
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Macular degeneration Benign:4
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJun 14, 2016- -
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJun 14, 2016- -
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJun 14, 2016- -
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJun 14, 2016- -
Complement component 2 deficiency Benign:2
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJun 14, 2016- -
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJun 14, 2016- -
not provided Benign:2
Benign, criteria provided, single submitterclinical testingInvitaeJan 31, 2024- -
Benign, criteria provided, single submitterclinical testingGeneDxJun 09, 2021This variant is associated with the following publications: (PMID: 21541267, 19255449, 19009711, 28173125, 33334325) -
Atypical hemolytic-uremic syndrome Benign:2
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJun 14, 2016- -
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJun 14, 2016- -
Atypical hemolytic-uremic syndrome with B factor anomaly;C3809653:Age related macular degeneration 14;C3809950:Complement factor b deficiency Benign:1
Likely benign, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsMay 09, 2022- -
Atypical hemolytic-uremic syndrome with B factor anomaly Benign:1
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaApr 27, 2017This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -
CFB-related condition Benign:1
Benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesJul 02, 2019This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -
Focal segmental glomerulosclerosis Benign:1
Benign, criteria provided, single submitterclinical testingGenome Diagnostics Laboratory, The Hospital for Sick ChildrenSep 27, 2022- -
Factor B fast/slow polymorphism Benign:1
Benign, no assertion criteria providedliterature onlyOMIMOct 28, 2013- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.084
BayesDel_addAF
Benign
-0.47
T
BayesDel_noAF
Benign
-0.30
Cadd
Benign
16
Dann
Uncertain
0.99
Eigen
Benign
-0.96
Eigen_PC
Benign
-1.1
FATHMM_MKL
Benign
0.13
N
LIST_S2
Benign
0.51
T;T;T
MetaRNN
Benign
0.0056
T;T;T
MetaSVM
Benign
-0.76
T
MutationTaster
Benign
1.0
P;P
PrimateAI
Benign
0.19
T
PROVEAN
Benign
-1.2
N;N;N
REVEL
Benign
0.28
Sift
Benign
0.033
D;D;D
Sift4G
Uncertain
0.013
D;D;D
Polyphen
0.98
.;.;D
Vest4
0.079
MPC
0.86
ClinPred
0.039
T
GERP RS
-4.9
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.0
Varity_R
0.044
gMVP
0.60

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.070
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs12614; hg19: chr6-31914179; COSMIC: COSV54959347; COSMIC: COSV54959347; API