chr6-32027390-G-A

Position:

chr6-32027390-G-A

Variant summary

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

The NM_001002029.4(C4B):c.2747G>A(p.Arg916Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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 0.00015 ( 1 hom., cov: 2)

Exomes 𝑓: 0.00031 ( 4 hom. )

Failed GnomAD Quality Control

Consequence

C4B
NM_001002029.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.145

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=0.01383099).

BS2

High Homozygotes in GnomAdExome4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
C4B	NM_001002029.4 linkuse as main transcript	c.2747G>A	p.Arg916Gln	missense_variant	21/41	ENST00000435363.7	NP_001002029.3	P0C0L4P0C0L5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
C4B	ENST00000435363.7 linkuse as main transcript	c.2747G>A	p.Arg916Gln	missense_variant	21/41	1	NM_001002029.4	ENSP00000415941.2		P0C0L5

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

39892

Hom.:

Cov.:

FAILED QC

Gnomad AFR

AF:

0.00131

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.000524

AC:

AN:

81992

Hom.:

AF XY:

0.000409

AC XY:

AN XY:

44012

show subpopulations

Gnomad AFR exome

AF:

0.00727

Gnomad AMR exome

AF:

0.00113

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:

0.00

GnomAD4 exome

AF:

0.000314

AC:

209

AN:

666592

Hom.:

Cov.:

AF XY:

0.000302

AC XY:

100

AN XY:

330652

show subpopulations

Gnomad4 AFR exome

AF:

0.0159

Gnomad4 AMR exome

AF:

0.00209

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000315

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000370

Gnomad4 OTH exome

AF:

0.000835

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000150

AC:

AN:

39886

Hom.:

Cov.:

AF XY:

0.000270

AC XY:

AN XY:

18534

show subpopulations

Gnomad4 AFR

AF:

0.00131

Gnomad4 AMR

AF:

0.00

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:

0.00388

Hom.:

ExAC

AF:

0.000125

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

May 04, 2022

The c.2747G>A (p.R916Q) alteration is located in exon 21 (coding exon 21) of the C4B gene. This alteration results from a G to A substitution at nucleotide position 2747, causing the arginine (R) at amino acid position 916 to be replaced by a glutamine (Q). 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

0.093

BayesDel_addAF

Benign

-0.64

BayesDel_noAF

Benign

-0.69

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.011

T;T

Eigen

Benign

-0.23

Eigen_PC

Benign

-0.090

FATHMM_MKL

Benign

0.49

M_CAP

Benign

0.0071

MetaRNN

Benign

0.014

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.9

L;.

PROVEAN

Benign

-0.85

N;N

REVEL

Benign

0.078

Sift

Benign

0.38

T;T

Sift4G

Benign

0.37

T;T

Polyphen

0.022

.;B

Vest4

0.079

MutPred

0.45

Loss of methylation at R916 (P = 0.0121);Loss of methylation at R916 (P = 0.0121);

MVP

0.19

ClinPred

0.021

GERP RS

2.6

Varity_R

0.11

gMVP

0.42

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