rs2230214

Variant names:

• chr9-121020021-G-A
• rs2230214
• NM_001735.3:c.1461C>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_001735.3(C5):​c.1461C>T​(p.Thr487Thr) 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:5
• Conservation: PhyloP100: 0.0620
• Publications: 14 publications found

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]

C5 Gene-Disease associations (from GenCC):

• complement component 5 deficiency

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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 rank	MANE	Protein	UniProt
C5	NM_001735.3	c.1461C>T	p.Thr487Thr	synonymous_variant	Exon 12 of 41	ENST00000223642.3	NP_001726.2
C5	NM_001317163.2	c.1479C>T	p.Thr493Thr	synonymous_variant	Exon 12 of 41		NP_001304092.1
C5	NM_001317164.2	c.1461C>T	p.Thr487Thr	synonymous_variant	Exon 12 of 21		NP_001304093.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
C5	ENST00000223642.3	c.1461C>T	p.Thr487Thr	synonymous_variant	Exon 12 of 41	1	NM_001735.3	ENSP00000223642.1

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

GnomAD2 exomes AF: 0.0905 AC: 22746 AN: 251272 AF XY: 0.0897

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 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

African (AFR) AF: 0.141 AC: 4645 AN: 32994

American (AMR) AF: 0.0687 AC: 3072 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.0617 AC: 1611 AN: 26092

East Asian (EAS) AF: 0.0286 AC: 1134 AN: 39656

South Asian (SAS) AF: 0.0804 AC: 6924 AN: 86142

European-Finnish (FIN) AF: 0.0648 AC: 3462 AN: 53408

Middle Eastern (MID) AF: 0.0648 AC: 373 AN: 5756

European-Non Finnish (NFE) AF: 0.108 AC: 120029 AN: 1106580

Other (OTH) AF: 0.0961 AC: 5783 AN: 60164

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

African (AFR) AF: 0.141 AC: 5834 AN: 41450

American (AMR) AF: 0.0778 AC: 1188 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.0591 AC: 205 AN: 3468

East Asian (EAS) AF: 0.0322 AC: 167 AN: 5186

South Asian (SAS) AF: 0.0912 AC: 439 AN: 4814

European-Finnish (FIN) AF: 0.0624 AC: 659 AN: 10566

Middle Eastern (MID) AF: 0.0816 AC: 24 AN: 294

European-Non Finnish (NFE) AF: 0.109 AC: 7400 AN: 67992

Other (OTH) AF: 0.0819 AC: 173 AN: 2112

Alfa AF: 0.108 Hom.: 677

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:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Nov 27, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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 -

C5-related disorder Benign:1

Apr 01, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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
PhyloP100		0.062
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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