6-31946402-C-T

Variant names:

• chr6-31946402-C-T
• rs12614
• NM_001710.6:c.94C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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. 14/21 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. R32L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.17 (3028 hom., cov: 32)
  • Exomes 𝑓: 0.10 (10014 hom.)
• Consequence: CFB NM_001710.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:16
• Conservation: PhyloP100: -0.787
• Publications: 109 publications found

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]

CFB Gene-Disease associations (from GenCC):

• atypical hemolytic-uremic syndrome with B factor anomaly

  Inheritance: Unknown, AD Classification: STRONG, MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics
• complement factor b deficiency

  Inheritance: AR Classification: MODERATE Submitted by: Ambry Genetics
• C3 glomerulonephritis

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ENSG00000244255 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 16076.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.325 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001710.6. 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
	CFB	NM_001710.6	MANE Select	c.94C>T	p.Arg32Trp	missense	Exon 2 of 18	NP_001701.2	P00751-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFB	ENST00000425368.7	TSL:1 MANE Select	c.94C>T	p.Arg32Trp	missense	Exon 2 of 18	ENSP00000416561.2	P00751-1
	ENSG00000244255	ENST00000456570.5	TSL:2	c.1600C>T	p.Arg534Trp	missense	Exon 14 of 30	ENSP00000410815.1	B4E1Z4
	CFB	ENST00000885733.1		c.94C>T	p.Arg32Trp	missense	Exon 2 of 18	ENSP00000555792.1

Frequencies

GnomAD3 genomes AF: 0.170 AC: 25908 AN: 152038 Hom.: 3019 Cov.: 32

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

GnomAD2 exomes AF: 0.124 AC: 30666 AN: 246544 AF XY: 0.127

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 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

African (AFR) AF: 0.341 AC: 11409 AN: 33480

American (AMR) AF: 0.0955 AC: 4272 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0939 AC: 2455 AN: 26136

East Asian (EAS) AF: 0.0695 AC: 2761 AN: 39700

South Asian (SAS) AF: 0.204 AC: 17605 AN: 86252

European-Finnish (FIN) AF: 0.152 AC: 7953 AN: 52310

Middle Eastern (MID) AF: 0.195 AC: 1122 AN: 5768

European-Non Finnish (NFE) AF: 0.0860 AC: 95622 AN: 1111980

Other (OTH) AF: 0.108 AC: 6535 AN: 60386

GnomAD4 genome AF: 0.171 AC: 25960 AN: 152156 Hom.: 3028 Cov.: 32 AF XY: 0.174 AC XY: 12949 AN XY: 74388

African (AFR) AF: 0.329 AC: 13658 AN: 41480

American (AMR) AF: 0.145 AC: 2216 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0897 AC: 311 AN: 3468

East Asian (EAS) AF: 0.0612 AC: 317 AN: 5180

South Asian (SAS) AF: 0.190 AC: 916 AN: 4818

European-Finnish (FIN) AF: 0.167 AC: 1775 AN: 10600

Middle Eastern (MID) AF: 0.187 AC: 55 AN: 294

European-Non Finnish (NFE) AF: 0.0923 AC: 6274 AN: 68000

Other (OTH) AF: 0.169 AC: 356 AN: 2108

Alfa AF: 0.113 Hom.: 5519

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

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	Macular degeneration (4)
-	-	3	Atypical hemolytic-uremic syndrome (3)
-	-	2	Complement component 2 deficiency (2)
-	-	2	not provided (2)
-	-	1	Atypical hemolytic-uremic syndrome with B factor anomaly (1)
-	-	1	Atypical hemolytic-uremic syndrome with B factor anomaly;C3809653:Age related macular degeneration 14;C3809950:Complement factor b deficiency (1)
-	-	1	CFB-related disorder (1)
-	-	1	Factor B fast/slow polymorphism (1)
-	-	1	Focal segmental glomerulosclerosis (1)

Computational scores

Source: dbNSFP v4.9

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
DEOGEN2	Benign	0.041	T
Eigen	Benign	-0.96
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.51	T
MetaRNN	Benign	0.0056	T
MetaSVM	Benign	-0.76	T
MutationAssessor	Benign	0.55	N
PhyloP100		-0.79
PrimateAI	Benign	0.19	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.28
Sift	Benign	0.033	D
Sift4G	Uncertain	0.013	D
Polyphen		0.98	D
Vest4		0.079
MPC		0.86
ClinPred		0.039	T
GERP RS		-4.9
PromoterAI		-0.019	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.044
gMVP		0.60
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

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