6-32027012-C-T

Position:

chr6-32027012-C-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 1P and 8B. PP2BP4_StrongBS2

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

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.717

Variant links:

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]

C4B links:

C4B (HGNC:):

C4B links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), C4B. . Gene score misZ 2.0154 (greater than the threshold 3.09). Trascript score misZ 4.2643 (greater than threshold 3.09). GenCC has associacion of gene with complement component 4b deficiency.

BP4

Computational evidence support a benign effect (MetaRNN=0.017967403).

BS2

High Homozygotes in GnomAdExome4 at 81 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
C4B	NM_001002029.4 linkuse as main transcript	c.2482C>T	p.Arg828Trp	missense_variant	20/41	ENST00000435363.7	NP_001002029.3	P0C0L4P0C0L5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
C4B	ENST00000435363.7 linkuse as main transcript	c.2482C>T	p.Arg828Trp	missense_variant	20/41	1	NM_001002029.4	ENSP00000415941.2	P0C0L5
C4B	ENST00000425700.3 linkuse as main transcript	c.2482C>T	p.Arg828Trp	missense_variant	20/40	1		ENSP00000391933.2	F5GXS0
C4B	ENST00000647698.1 linkuse as main transcript	c.1186C>T	p.Arg396Trp	missense_variant	10/31			ENSP00000497270.1	A0A3B3ISA6
C4B	ENST00000648821.1 linkuse as main transcript	n.916C>T		non_coding_transcript_exon_variant	8/27

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

104286

Hom.:

Cov.:

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.:

AF XY:

0.000663

AC XY:

AN XY:

114660

show subpopulations

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.:

Cov.:

AF XY:

0.000451

AC XY:

308

AN XY:

682712

show subpopulations

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:

AN:

104370

Hom.:

Cov.:

AF XY:

0.000222

AC XY:

AN XY:

49642

show subpopulations

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.:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000129

AC:

ExAC

AF:

0.000731

AC:

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

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

BayesDel_noAF

Benign

-0.35

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.16

T;T

Eigen

Uncertain

0.20

Eigen_PC

Benign

0.0024

FATHMM_MKL

Benign

0.030

MetaRNN

Benign

0.018

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Pathogenic

3.3

M;.

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

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

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

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over