6-32027332-G-C

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2BP4_ModerateBS2

The NM_001002029.4(C4B):c.2689G>C(p.Val897Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000097 ( 2 hom., cov: 4)

Exomes 𝑓: 0.000017 ( 7 hom. )

Failed GnomAD Quality Control

Consequence

C4B
NM_001002029.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.61

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 Likely_benign. Variant got -5 ACMG points.

PP2

Missense variant where missense usually causes diseases, C4B

BP4

Computational evidence support a benign effect (MetaRNN=0.1712833).

BS2

High Homozygotes in GnomAdExome at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
C4B	NM_001002029.4 linkuse as main transcript	c.2689G>C	p.Val897Leu	missense_variant	21/41	ENST00000435363.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
C4B	ENST00000435363.7 linkuse as main transcript	c.2689G>C	p.Val897Leu	missense_variant	21/41	1	NM_001002029.4	P1

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

41274

Hom.:

Cov.:

FAILED QC

Gnomad AFR

AF:

0.00

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:

0.000145

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000672

AC:

AN:

89294

Hom.:

AF XY:

0.0000410

AC XY:

AN XY:

48834

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.000123

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000166

AC:

AN:

842226

Hom.:

Cov.:

AF XY:

0.0000142

AC XY:

AN XY:

423092

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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:

0.0000215

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000969

AC:

AN:

41274

Hom.:

Cov.:

AF XY:

0.000103

AC XY:

AN XY:

19332

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.000145

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.0000339

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

Dec 06, 2021

The c.2689G>C (p.V897L) alteration is located in exon 21 (coding exon 21) of the C4B gene. This alteration results from a G to C substitution at nucleotide position 2689, causing the valine (V) at amino acid position 897 to be replaced by a leucine (L). 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

0.23

BayesDel_addAF

Benign

-0.085

BayesDel_noAF

Benign

-0.36

Cadd

Benign

Dann

Uncertain

1.0

DEOGEN2

Benign

0.051

T;T

Eigen

Benign

0.11

Eigen_PC

Benign

0.14

FATHMM_MKL

Uncertain

0.84

M_CAP

Benign

0.012

MetaRNN

Benign

0.17

T;T

MetaSVM

Benign

-0.93

MutationAssessor

Uncertain

2.6

M;.

MutationTaster

Benign

1.0

D;D

PROVEAN

Benign

-2.2

N;N

REVEL

Benign

0.12

Sift

Uncertain

0.0080

D;D

Sift4G

Uncertain

0.013

D;D

Polyphen

0.60

.;P

Vest4

0.41

MutPred

0.36

Loss of catalytic residue at V897 (P = 0.0674);Loss of catalytic residue at V897 (P = 0.0674);

MVP

0.29

ClinPred

0.37

GERP RS

3.6

Varity_R

0.51

gMVP

0.68

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

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