rs2241394

Variant names:

• chr19-6685219-G-C
• rs2241394
• NM_000064.4:c.3811-73C>G

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.3811-73C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.121 in 1,417,662 control chromosomes in the GnomAD database, including 11,259 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.10 (992 hom., cov: 32)
  • Exomes 𝑓: 0.12 (10267 hom.)
• Consequence: C3 NM_000064.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3 O:1
• Conservation: PhyloP100: 0.606
• Publications: 28 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

ENSG00000297005 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 19-6685219-G-C is Benign according to our data. Variant chr19-6685219-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 162178.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.126 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
C3	NM_000064.4	c.3811-73C>G		intron_variant	Intron 29 of 40	ENST00000245907.11	NP_000055.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
C3	ENST00000245907.11	c.3811-73C>G		intron_variant	Intron 29 of 40	1	NM_000064.4	ENSP00000245907.4

Frequencies

GnomAD3 genomes AF: 0.104 AC: 15835 AN: 152048 Hom.: 989 Cov.: 32

Gnomad AFR AF: 0.0469

Gnomad AMI AF: 0.141

Gnomad AMR AF: 0.106

Gnomad ASJ AF: 0.161

Gnomad EAS AF: 0.0795

Gnomad SAS AF: 0.0605

Gnomad FIN AF: 0.181

Gnomad MID AF: 0.0728

Gnomad NFE AF: 0.128

Gnomad OTH AF: 0.112

GnomAD4 exome AF: 0.123 AC: 156028 AN: 1265496 Hom.: 10267 AF XY: 0.122 AC XY: 77303 AN XY: 635006

African (AFR) AF: 0.0426 AC: 1247 AN: 29298

American (AMR) AF: 0.0867 AC: 3352 AN: 38644

Ashkenazi Jewish (ASJ) AF: 0.154 AC: 3771 AN: 24504

East Asian (EAS) AF: 0.0762 AC: 2824 AN: 37064

South Asian (SAS) AF: 0.0635 AC: 5023 AN: 79046

European-Finnish (FIN) AF: 0.183 AC: 9320 AN: 50832

Middle Eastern (MID) AF: 0.0940 AC: 489 AN: 5204

European-Non Finnish (NFE) AF: 0.131 AC: 123644 AN: 947148

Other (OTH) AF: 0.118 AC: 6358 AN: 53756

GnomAD4 genome AF: 0.104 AC: 15855 AN: 152166 Hom.: 992 Cov.: 32 AF XY: 0.105 AC XY: 7831 AN XY: 74386

African (AFR) AF: 0.0473 AC: 1964 AN: 41534

American (AMR) AF: 0.105 AC: 1612 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.161 AC: 557 AN: 3470

East Asian (EAS) AF: 0.0793 AC: 411 AN: 5180

South Asian (SAS) AF: 0.0603 AC: 291 AN: 4824

European-Finnish (FIN) AF: 0.181 AC: 1914 AN: 10588

Middle Eastern (MID) AF: 0.0782 AC: 23 AN: 294

European-Non Finnish (NFE) AF: 0.128 AC: 8721 AN: 67984

Other (OTH) AF: 0.111 AC: 234 AN: 2104

Alfa AF: 0.118 Hom.: 161

Bravo AF: 0.0978

Asia WGS AF: 0.0630 AC: 219 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2 Other:1

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Department of Ophthalmology and Visual Sciences Kyoto University

Significance: not provided

Review Status: no classification provided

Collection Method: not provided

- -

Jun 19, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 22174912) -

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Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Kidney disorder Benign:1

Dec 12, 2016

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	11
DANN	Benign	0.56
PhyloP100		0.61
PromoterAI		0.026	Neutral
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: rs2241394; hg19: chr19-6685230; COSMIC: COSV107196160; COSMIC: COSV107196160;