rs2230214

chr9-121020021-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001735.3(C5):c.1461C>T(p.Thr487=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.101 in 1,607,578 control chromosomes in the GnomAD database, including 9,074 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (914 hom., cov: 32)
  • Exomes 𝑓: 0.10 (8160 hom.)
• Consequence: C5 NM_001735.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.0620

Genes affected

C5 (HGNC:1331): (complement C5) This gene encodes a component of the complement system, a part of the innate immune system that plays an important role in inflammation, host homeostasis, and host defense against pathogens. The encoded preproprotein is proteolytically processed to generate multiple protein products, including the C5 alpha chain, C5 beta chain, C5a anaphylatoxin and C5b. The C5 protein is comprised of the C5 alpha and beta chains, which are linked by a disulfide bridge. Cleavage of the alpha chain by a convertase enzyme results in the formation of the C5a anaphylatoxin, which possesses potent spasmogenic and chemotactic activity, and the C5b macromolecular cleavage product, a subunit of the membrane attack complex (MAC). Mutations in this gene cause complement component 5 deficiency, a disease characterized by recurrent bacterial infections. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2015]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.64).
• BP6: Variant 9-121020021-G-A is Benign according to our data. Variant chr9-121020021-G-A is described in ClinVar as [Benign]. Clinvar id is 402456.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.062 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.138 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
C5	NM_001735.3	c.1461C>T	p.Thr487=	synonymous_variant	12/41	ENST00000223642.3
C5	NM_001317163.2	c.1479C>T	p.Thr493=	synonymous_variant	12/41
C5	NM_001317164.2	c.1461C>T	p.Thr487=	synonymous_variant	12/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
C5	ENST00000223642.3	c.1461C>T	p.Thr487=	synonymous_variant	12/41	1	NM_001735.3	P1

Frequencies

GnomAD3 genomes AF: 0.106 AC: 16117 AN: 151954 Hom.: 914 Cov.: 32

Gnomad AFR AF: 0.141

Gnomad AMI AF: 0.0351

Gnomad AMR AF: 0.0781

Gnomad ASJ AF: 0.0591

Gnomad EAS AF: 0.0325

Gnomad SAS AF: 0.0911

Gnomad FIN AF: 0.0624

Gnomad MID AF: 0.0728

Gnomad NFE AF: 0.109

Gnomad OTH AF: 0.0823

GnomAD3 exomes AF: 0.0905 AC: 22746 AN: 251272 Hom.: 1240 AF XY: 0.0897 AC XY: 12176 AN XY: 135816

Gnomad AFR exome AF: 0.147

Gnomad AMR exome AF: 0.0682

Gnomad ASJ exome AF: 0.0650

Gnomad EAS exome AF: 0.0354

Gnomad SAS exome AF: 0.0809

Gnomad FIN exome AF: 0.0607

Gnomad NFE exome AF: 0.109

Gnomad OTH exome AF: 0.0854

GnomAD4 exome AF: 0.101 AC: 147033 AN: 1455506 Hom.: 8160 Cov.: 30 AF XY: 0.100 AC XY: 72639 AN XY: 724524

Gnomad4 AFR exome AF: 0.141

Gnomad4 AMR exome AF: 0.0687

Gnomad4 ASJ exome AF: 0.0617

Gnomad4 EAS exome AF: 0.0286

Gnomad4 SAS exome AF: 0.0804

Gnomad4 FIN exome AF: 0.0648

Gnomad4 NFE exome AF: 0.108

Gnomad4 OTH exome AF: 0.0961

GnomAD4 genome AF: 0.106 AC: 16121 AN: 152072 Hom.: 914 Cov.: 32 AF XY: 0.104 AC XY: 7701 AN XY: 74330

Gnomad4 AFR AF: 0.141

Gnomad4 AMR AF: 0.0778

Gnomad4 ASJ AF: 0.0591

Gnomad4 EAS AF: 0.0322

Gnomad4 SAS AF: 0.0912

Gnomad4 FIN AF: 0.0624

Gnomad4 NFE AF: 0.109

Gnomad4 OTH AF: 0.0819

Alfa AF: 0.107 Hom.: 645

Bravo AF: 0.108

Asia WGS AF: 0.0670 AC: 232 AN: 3478

EpiCase AF: 0.105

EpiControl AF: 0.104

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 27, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 28, 2016

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 -

C5-related condition Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 01, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
Cadd	Benign	5.2
Dann	Benign	0.47

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

Other links and lift over

dbSNP: rs2230214; hg19: chr9-123782299; COSMIC: COSV56327421;