6-32028766-G-A

Variant summary

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

The NM_001002029.4(C4B):c.3304G>A(p.Glu1102Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000115 in 1,563,262 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00067 ( 5 hom., cov: 22)

Exomes 𝑓: 0.000060 ( 10 hom. )

Consequence

C4B
NM_001002029.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.52

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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=0.015834302).

BS2

High Homozygotes in GnomAd at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
C4B	NM_001002029.4 linkuse as main transcript	c.3304G>A	p.Glu1102Lys	missense_variant	26/41	ENST00000435363.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
C4B	ENST00000435363.7 linkuse as main transcript	c.3304G>A	p.Glu1102Lys	missense_variant	26/41	1	NM_001002029.4	P1
C4B	ENST00000425700.3 linkuse as main transcript	c.3304G>A	p.Glu1102Lys	missense_variant	26/40	1
C4B	ENST00000647698.1 linkuse as main transcript	c.2011G>A	p.Glu671Lys	missense_variant	16/31
C4B	ENST00000648821.1 linkuse as main transcript	n.1917G>A		non_coding_transcript_exon_variant	13/27

Frequencies

GnomAD3 genomes

AF:

0.000666

AC:

AN:

141074

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00229

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000487

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000187

AC:

AN:

240246

Hom.:

AF XY:

0.000107

AC XY:

AN XY:

130316

show subpopulations

Gnomad AFR exome

AF:

0.00279

Gnomad AMR exome

AF:

0.0000293

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000169

GnomAD4 exome

AF:

0.0000598

AC:

AN:

1422072

Hom.:

Cov.:

AF XY:

0.0000424

AC XY:

AN XY:

707730

show subpopulations

Gnomad4 AFR exome

AF:

0.00248

Gnomad4 AMR exome

AF:

0.0000453

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000340

GnomAD4 genome

AF:

0.000666

AC:

AN:

141190

Hom.:

Cov.:

AF XY:

0.000658

AC XY:

AN XY:

68358

show subpopulations

Gnomad4 AFR

AF:

0.00229

Gnomad4 AMR

AF:

0.000487

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000498

Hom.:

ESP6500AA

AF:

0.00196

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000228

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

Oct 12, 2021

The c.3304G>A (p.E1102K) alteration is located in exon 26 (coding exon 26) of the C4B gene. This alteration results from a G to A substitution at nucleotide position 3304, causing the glutamic acid (E) at amino acid position 1102 to be replaced by a lysine (K). 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

0.19

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.43

Cadd

Benign

Dann

Uncertain

1.0

DEOGEN2

Benign

0.013

T;T

Eigen

Benign

0.040

Eigen_PC

Benign

0.063

FATHMM_MKL

Uncertain

0.76

M_CAP

Benign

0.013

MetaRNN

Benign

0.016

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.6

L;.

MutationTaster

Benign

0.75

N;N

PROVEAN

Benign

-1.3

N;N

REVEL

Benign

0.079

Sift

Benign

0.063

T;T

Sift4G

Benign

0.14

T;D

Polyphen

0.70

.;P

Vest4

0.34

MVP

0.16

ClinPred

0.029

GERP RS

4.7

Varity_R

0.43

gMVP

0.45

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