rs8942

Positions:

• chr1-207096574-C-G
• chr1-207096574-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_001017365.3(C4BPB):​c.462C>G​(p.Asn154Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000688 in 1,454,448 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. N154N) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: C4BPB NM_001017365.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.376

Genes affected

C4BPB (HGNC:1328): (complement component 4 binding protein beta) This gene encodes a member of a superfamily of proteins composed predominantly of tandemly arrayed short consensus repeats of approximately 60 amino acids. A single, unique beta-chain encoded by this gene assembles with seven identical alpha-chains into the predominant isoform of C4b-binding protein, a multimeric protein that controls activation of the complement cascade through the classical pathway. C4b-binding protein has a regulatory role in the coagulation system also, mediated through the beta-chain binding of protein S, a vitamin K-dependent protein that serves as a cofactor of activated protein C. The genes encoding both alpha and beta chains are located adjacent to each other on human chromosome 1 in the regulator of complement activation gene cluster. Alternative splicing gives rise to multiple transcript variants. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM1: In a glycosylation_site N-linked (GlcNAc...) asparagine (size 0) in uniprot entity C4BPB_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.11915648).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
C4BPB	NM_001017365.3	c.462C>G	p.Asn154Lys	missense_variant	5/7	ENST00000367078.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
C4BPB	ENST00000367078.8	c.462C>G	p.Asn154Lys	missense_variant	5/7	1	NM_001017365.3	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000400 AC: 1 AN: 249976 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135118

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: 0.00

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 6.88e-7 AC: 1 AN: 1454448 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 724092

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: 0.0000187

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	15
DANN	Benign	0.75
DEOGEN2	Benign	0.077	T;T;T;.;T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.020	N
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.12	T;T;T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.1	L;.;L;.;L
MutationTaster	Benign	1.0	P;P;P;P
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-1.0	N;N;N;N;N
REVEL	Benign	0.056
Sift	Benign	0.15	T;T;T;T;T
Sift4G	Uncertain	0.057	T;T;T;T;T
Polyphen		0.41	B;.;B;B;B
Vest4		0.15
MutPred		0.58		Gain of methylation at N154 (P = 0.0055);Gain of methylation at N154 (P = 0.0055);Gain of methylation at N154 (P = 0.0055);.;Gain of methylation at N154 (P = 0.0055);
MVP		0.048
MPC		0.19
ClinPred		0.051	T
GERP RS		-2.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.046
gMVP		0.19

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs8942; hg19: chr1-207269919;