chr19-6702146-C-G

Variant names:

• chr19-6702146-C-G
• rs428453
• NM_000064.4:c.2421G>C

Variant summary

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

The NM_000064.4(C3):​c.2421G>C​(p.Val807Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.638 in 1,595,750 control chromosomes in the GnomAD database, including 329,713 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.66 (33429 hom., cov: 32)
  • Exomes 𝑓: 0.64 (296284 hom.)
• Consequence: C3 NM_000064.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.138
• Publications: 36 publications found

Genes affected

C3 (HGNC:1318): (complement C3) Complement component C3 plays a central role in the activation of complement system. Its activation is required for both classical and alternative complement activation pathways. The encoded preproprotein is proteolytically processed to generate alpha and beta subunits that form the mature protein, which is then further processed to generate numerous peptide products. The C3a peptide, also known as the C3a anaphylatoxin, modulates inflammation and possesses antimicrobial activity. Mutations in this gene are associated with atypical hemolytic uremic syndrome and age-related macular degeneration in human patients. [provided by RefSeq, Nov 2015]

C3 Gene-Disease associations (from GenCC):

• atypical hemolytic-uremic syndrome with C3 anomaly

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen
• complement component 3 deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Laboratory for Molecular Medicine
• C3 glomerulonephritis

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.62).
• BP6: Variant 19-6702146-C-G is Benign according to our data. Variant chr19-6702146-C-G is described in ClinVar as [Benign]. Clinvar id is 330305.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.138 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.821 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
C3	NM_000064.4	c.2421G>C	p.Val807Val	synonymous_variant	Exon 19 of 41	ENST00000245907.11	NP_000055.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
C3	ENST00000245907.11	c.2421G>C	p.Val807Val	synonymous_variant	Exon 19 of 41	1	NM_000064.4	ENSP00000245907.4

Frequencies

GnomAD3 genomes AF: 0.659 AC: 100195 AN: 151948 Hom.: 33391 Cov.: 32

Gnomad AFR AF: 0.704

Gnomad AMI AF: 0.444

Gnomad AMR AF: 0.736

Gnomad ASJ AF: 0.613

Gnomad EAS AF: 0.841

Gnomad SAS AF: 0.713

Gnomad FIN AF: 0.569

Gnomad MID AF: 0.674

Gnomad NFE AF: 0.616

Gnomad OTH AF: 0.676

GnomAD2 exomes AF: 0.674 AC: 168682 AN: 250406 AF XY: 0.666

Gnomad AFR exome AF: 0.705

Gnomad AMR exome AF: 0.811

Gnomad ASJ exome AF: 0.597

Gnomad EAS exome AF: 0.838

Gnomad FIN exome AF: 0.563

Gnomad NFE exome AF: 0.619

Gnomad OTH exome AF: 0.664

GnomAD4 exome AF: 0.636 AC: 918576 AN: 1443684 Hom.: 296284 Cov.: 30 AF XY: 0.637 AC XY: 458040 AN XY: 719452

African (AFR) AF: 0.711 AC: 23444 AN: 32960

American (AMR) AF: 0.800 AC: 35769 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.592 AC: 15390 AN: 25998

East Asian (EAS) AF: 0.865 AC: 34281 AN: 39612

South Asian (SAS) AF: 0.706 AC: 60665 AN: 85896

European-Finnish (FIN) AF: 0.565 AC: 29470 AN: 52146

Middle Eastern (MID) AF: 0.673 AC: 3845 AN: 5712

European-Non Finnish (NFE) AF: 0.617 AC: 676951 AN: 1096832

Other (OTH) AF: 0.648 AC: 38761 AN: 59834

GnomAD4 genome AF: 0.660 AC: 100290 AN: 152066 Hom.: 33429 Cov.: 32 AF XY: 0.662 AC XY: 49190 AN XY: 74350

African (AFR) AF: 0.705 AC: 29223 AN: 41452

American (AMR) AF: 0.736 AC: 11245 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.613 AC: 2126 AN: 3468

East Asian (EAS) AF: 0.842 AC: 4354 AN: 5174

South Asian (SAS) AF: 0.712 AC: 3437 AN: 4828

European-Finnish (FIN) AF: 0.569 AC: 6013 AN: 10572

Middle Eastern (MID) AF: 0.673 AC: 198 AN: 294

European-Non Finnish (NFE) AF: 0.616 AC: 41869 AN: 67982

Other (OTH) AF: 0.672 AC: 1422 AN: 2116

Alfa AF: 0.635 Hom.: 20753

Bravo AF: 0.675

Asia WGS AF: 0.765 AC: 2659 AN: 3478

EpiCase AF: 0.635

EpiControl AF: 0.633

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Age related macular degeneration 9 Benign:2

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:2

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

- -

Complement component 3 deficiency Benign:2

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Atypical hemolytic-uremic syndrome with C3 anomaly Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
CADD	Benign	7.2
DANN	Benign	0.69
PhyloP100		0.14
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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: rs428453; hg19: chr19-6702157; COSMIC: COSV55573154; COSMIC: COSV55573154;