rs2230199

Variant names:

• chr19-6718376-G-C
• rs2230199
• NM_000064.4:c.304C>G

Your query was ambiguous. Multiple possible variants found:

• chr19-6718376-G-C
• chr19-6718376-G-A
• chr19-6718376-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000064.4(C3):​c.304C>G​(p.Arg102Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.187 in 1,614,024 control chromosomes in the GnomAD database, including 31,345 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R102H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.14 (2011 hom., cov: 32)
  • Exomes 𝑓: 0.19 (29334 hom.)
• Consequence: C3 NM_000064.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8 O:1
• Conservation: PhyloP100: -0.00200
• Publications: 443 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: ClinGen, Labcorp Genetics (formerly Invitae)
• complement component 3 deficiency

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

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0028393269).
• BP6: Variant 19-6718376-G-C is Benign according to our data. Variant chr19-6718376-G-C is described in ClinVar as Benign. ClinVar VariationId is 17056.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.205 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000064.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C3	NM_000064.4	MANE Select	c.304C>G	p.Arg102Gly	missense	Exon 3 of 41	NP_000055.2	P01024

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C3	ENST00000245907.11	TSL:1 MANE Select	c.304C>G	p.Arg102Gly	missense	Exon 3 of 41	ENSP00000245907.4	P01024
	C3	ENST00000952696.1		c.304C>G	p.Arg102Gly	missense	Exon 3 of 42	ENSP00000622755.1
	C3	ENST00000879543.1		c.304C>G	p.Arg102Gly	missense	Exon 3 of 41	ENSP00000549602.1

Frequencies

GnomAD3 genomes AF: 0.141 AC: 21517 AN: 152112 Hom.: 2011 Cov.: 32

Gnomad AFR AF: 0.0473

Gnomad AMI AF: 0.0647

Gnomad AMR AF: 0.114

Gnomad ASJ AF: 0.207

Gnomad EAS AF: 0.000964

Gnomad SAS AF: 0.124

Gnomad FIN AF: 0.181

Gnomad MID AF: 0.177

Gnomad NFE AF: 0.208

Gnomad OTH AF: 0.141

GnomAD2 exomes AF: 0.150 AC: 37843 AN: 251466 AF XY: 0.155

Gnomad AFR exome AF: 0.0442

Gnomad AMR exome AF: 0.0825

Gnomad ASJ exome AF: 0.207

Gnomad EAS exome AF: 0.000815

Gnomad FIN exome AF: 0.175

Gnomad NFE exome AF: 0.206

Gnomad OTH exome AF: 0.168

GnomAD4 exome AF: 0.192 AC: 281032 AN: 1461794 Hom.: 29334 Cov.: 38 AF XY: 0.191 AC XY: 138972 AN XY: 727206

African (AFR) AF: 0.0392 AC: 1314 AN: 33480

American (AMR) AF: 0.0848 AC: 3791 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.209 AC: 5473 AN: 26134

East Asian (EAS) AF: 0.000655 AC: 26 AN: 39698

South Asian (SAS) AF: 0.130 AC: 11187 AN: 86252

European-Finnish (FIN) AF: 0.180 AC: 9629 AN: 53418

Middle Eastern (MID) AF: 0.155 AC: 895 AN: 5768

European-Non Finnish (NFE) AF: 0.214 AC: 237542 AN: 1111928

Other (OTH) AF: 0.185 AC: 11175 AN: 60392

GnomAD4 genome AF: 0.141 AC: 21521 AN: 152230 Hom.: 2011 Cov.: 32 AF XY: 0.139 AC XY: 10331 AN XY: 74414

African (AFR) AF: 0.0473 AC: 1964 AN: 41546

American (AMR) AF: 0.114 AC: 1739 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.207 AC: 720 AN: 3472

East Asian (EAS) AF: 0.000966 AC: 5 AN: 5176

South Asian (SAS) AF: 0.126 AC: 606 AN: 4826

European-Finnish (FIN) AF: 0.181 AC: 1921 AN: 10584

Middle Eastern (MID) AF: 0.180 AC: 53 AN: 294

European-Non Finnish (NFE) AF: 0.208 AC: 14160 AN: 68006

Other (OTH) AF: 0.139 AC: 294 AN: 2114

Alfa AF: 0.198 Hom.: 2614

Bravo AF: 0.131

ESP6500AA AF: 0.0481 AC: 212

ESP6500EA AF: 0.209 AC: 1801

ExAC AF: 0.152 AC: 18427

Asia WGS AF: 0.0590 AC: 207 AN: 3478

EpiCase AF: 0.209

EpiControl AF: 0.205

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Age related macular degeneration 9 (1)
-	-	1	Atypical hemolytic-uremic syndrome;C3151071:Complement component 3 deficiency;C4055342:C3 glomerulonephritis (1)
-	-	1	C3S/C3F POLYMORPHISM (1)
-	-	1	Focal segmental glomerulosclerosis (1)
-	-	1	Inborn genetic diseases (1)
-	-	-	MACULAR DEGENERATION, AGE-RELATED, 9, SUSCEPTIBILITY TO (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	9.9
DANN	Benign	0.56
DEOGEN2	Benign	0.080	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.061	N
LIST_S2	Benign	0.38	T
MetaRNN	Benign	0.0028	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.20	N
PhyloP100		-0.0020
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.068
Sift	Benign	0.40	T
Sift4G	Benign	0.38	T
Polyphen		0.0	B
Vest4		0.034
MPC		0.75
ClinPred		0.0036	T
GERP RS		-0.59
Varity_R		0.59
gMVP		0.72
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2230199; hg19: chr19-6718387; COSMIC: COSV55573165; COSMIC: COSV55573165;