6-32027012-C-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 1P and 8B. PP2 BP4_Strong BS2

The NM_001002029.4(C4B):c.2482C>T(p.Arg828Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000441 in 1,369,690 control chromosomes in the GnomAD database, including 81 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00028 (2 hom., cov: 17)
  • Exomes 𝑓: 0.00044 (81 hom.)
  • Failed GnomAD Quality Control
• Consequence: C4B NM_001002029.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.717

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]

ACMG classification

Verdict is Benign. Variant got -7 ACMG points.

• PP2: Missense variant where missense usually causes diseases, C4B
• BP4: Computational evidence support a benign effect (MetaRNN=0.017967403).
• BS2: High Homozygotes in GnomAdExome at 21 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
C4B	NM_001002029.4	c.2482C>T	p.Arg828Trp	missense_variant	20/41	ENST00000435363.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
C4B	ENST00000435363.7	c.2482C>T	p.Arg828Trp	missense_variant	20/41	1	NM_001002029.4	P1
C4B	ENST00000425700.3	c.2482C>T	p.Arg828Trp	missense_variant	20/40	1
C4B	ENST00000647698.1	c.1189C>T	p.Arg397Trp	missense_variant	10/31
C4B	ENST00000648821.1	n.916C>T		non_coding_transcript_exon_variant	8/27

Frequencies

GnomAD3 genomes AF: 0.00 AC: 28 AN: 104286 Hom.: 2 Cov.: 17 FAILED QC

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000988

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00527

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000376

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000220

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000681 AC: 143 AN: 209836 Hom.: 21 AF XY: 0.000663 AC XY: 76 AN XY: 114660

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000307

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00661

Gnomad SAS exome AF: 0.0000353

Gnomad FIN exome AF: 0.000564

Gnomad NFE exome AF: 0.000298

Gnomad OTH exome AF: 0.000188

GnomAD4 exome AF: 0.000441 AC: 604 AN: 1369690 Hom.: 81 Cov.: 31 AF XY: 0.000451 AC XY: 308 AN XY: 682712

Gnomad4 AFR exome AF: 0.0000301

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0109

Gnomad4 SAS exome AF: 0.0000360

Gnomad4 FIN exome AF: 0.000422

Gnomad4 NFE exome AF: 0.000155

Gnomad4 OTH exome AF: 0.000176

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.000278 AC: 29 AN: 104370 Hom.: 2 Cov.: 17 AF XY: 0.000222 AC XY: 11 AN XY: 49642

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000987

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00563

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000376

Gnomad4 NFE AF: 0.000220

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000186 Hom.: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000129 AC: 1

ExAC AF: 0.000731 AC: 85

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 08, 2022

The c.2482C>T (p.R828W) alteration is located in exon 20 (coding exon 20) of the C4B gene. This alteration results from a C to T substitution at nucleotide position 2482, causing the arginine (R) at amino acid position 828 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.35
Cadd	Uncertain	26
Dann	Uncertain	1.0
DEOGEN2	Benign	0.16	T;T
Eigen	Uncertain	0.20
Eigen_PC	Benign	0.0024
FATHMM_MKL	Benign	0.030	N
MetaRNN	Benign	0.018	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Pathogenic	3.3	M;.
MutationTaster	Benign	1.0	N;N
PROVEAN	Uncertain	-3.6	D;D
REVEL	Benign	0.10
Sift	Uncertain	0.0020	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	.;D
Vest4		0.49
MVP		0.49
ClinPred		0.14	T
GERP RS		3.5
Varity_R		0.33
gMVP		0.76

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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

Other links and lift over

dbSNP: rs374713901; hg19: chr6-31994789;