1-207096574-C-T

Variant names:

• chr1-207096574-C-T
• rs8942
• NM_001017365.3:c.462C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001017365.3(C4BPB):​c.462C>T​(p.Asn154Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.206 in 1,600,706 control chromosomes in the GnomAD database, including 49,889 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.36 (15180 hom., cov: 32)
  • Exomes 𝑓: 0.19 (34709 hom.)
• Consequence: C4BPB NM_001017365.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.376
• Publications: 32 publications found

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

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 1-207096574-C-T is Benign according to our data. Variant chr1-207096574-C-T is described in ClinVar as Benign. ClinVar VariationId is 402449.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.376 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.775 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
C4BPB	NM_001017365.3	c.462C>T	p.Asn154Asn	synonymous_variant	Exon 5 of 7	ENST00000367078.8	NP_001017365.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
C4BPB	ENST00000367078.8	c.462C>T	p.Asn154Asn	synonymous_variant	Exon 5 of 7	1	NM_001017365.3	ENSP00000356045.3

Frequencies

GnomAD3 genomes AF: 0.356 AC: 54112 AN: 151998 Hom.: 15136 Cov.: 32

Gnomad AFR AF: 0.782

Gnomad AMI AF: 0.214

Gnomad AMR AF: 0.297

Gnomad ASJ AF: 0.271

Gnomad EAS AF: 0.165

Gnomad SAS AF: 0.244

Gnomad FIN AF: 0.116

Gnomad MID AF: 0.354

Gnomad NFE AF: 0.177

Gnomad OTH AF: 0.343

GnomAD2 exomes AF: 0.231 AC: 57747 AN: 249976 AF XY: 0.224

Gnomad AFR exome AF: 0.795

Gnomad AMR exome AF: 0.215

Gnomad ASJ exome AF: 0.276

Gnomad EAS exome AF: 0.162

Gnomad FIN exome AF: 0.114

Gnomad NFE exome AF: 0.179

Gnomad OTH exome AF: 0.221

GnomAD4 exome AF: 0.190 AC: 275887 AN: 1448590 Hom.: 34709 Cov.: 28 AF XY: 0.192 AC XY: 138208 AN XY: 721386

African (AFR) AF: 0.809 AC: 26495 AN: 32740

American (AMR) AF: 0.223 AC: 9931 AN: 44614

Ashkenazi Jewish (ASJ) AF: 0.272 AC: 7064 AN: 25940

East Asian (EAS) AF: 0.180 AC: 7118 AN: 39564

South Asian (SAS) AF: 0.252 AC: 21583 AN: 85786

European-Finnish (FIN) AF: 0.117 AC: 6241 AN: 53382

Middle Eastern (MID) AF: 0.356 AC: 2045 AN: 5740

European-Non Finnish (NFE) AF: 0.165 AC: 181414 AN: 1100988

Other (OTH) AF: 0.234 AC: 13996 AN: 59836

GnomAD4 genome AF: 0.356 AC: 54212 AN: 152116 Hom.: 15180 Cov.: 32 AF XY: 0.348 AC XY: 25919 AN XY: 74390

African (AFR) AF: 0.782 AC: 32443 AN: 41462

American (AMR) AF: 0.297 AC: 4546 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.271 AC: 941 AN: 3470

East Asian (EAS) AF: 0.165 AC: 857 AN: 5180

South Asian (SAS) AF: 0.244 AC: 1176 AN: 4818

European-Finnish (FIN) AF: 0.116 AC: 1228 AN: 10602

Middle Eastern (MID) AF: 0.347 AC: 102 AN: 294

European-Non Finnish (NFE) AF: 0.177 AC: 12007 AN: 67986

Other (OTH) AF: 0.340 AC: 717 AN: 2110

Alfa AF: 0.262 Hom.: 18178

Bravo AF: 0.387

Asia WGS AF: 0.238 AC: 827 AN: 3478

EpiCase AF: 0.197

EpiControl AF: 0.192

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 09, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:1

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	1.2
DANN	Benign	0.46
PhyloP100		-0.38
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs8942; hg19: chr1-207269919; COSMIC: COSV54692228; COSMIC: COSV54692228;