rs17612

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001317163.2(C5):c.4329A>C(p.Glu1443Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.061 in 1,610,638 control chromosomes in the GnomAD database, including 3,483 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 (★★).

Frequency

Genomes: 𝑓 0.045 ( 230 hom., cov: 32)

Exomes 𝑓: 0.063 ( 3253 hom. )

Consequence

C5
NM_001317163.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -0.209

Publications

26 publications found

Variant links:

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)

C5 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (MetaRNN=0.0017857254).

BP6

Variant 9-120963648-T-G is Benign according to our data. Variant chr9-120963648-T-G is described in ClinVar as Benign. ClinVar VariationId is 402451.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0672 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001317163.2. 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
	C5	NM_001735.3	MANE Select	c.4311A>C	p.Glu1437Asp	missense	Exon 34 of 41	NP_001726.2
	C5	NM_001317163.2		c.4329A>C	p.Glu1443Asp	missense	Exon 34 of 41	NP_001304092.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
C5	ENST00000223642.3	TSL:1 MANE Select	c.4311A>C	p.Glu1437Asp	missense	Exon 34 of 41	ENSP00000223642.1
C5	ENST00000696281.1		c.4329A>C	p.Glu1443Asp	missense	Exon 34 of 42	ENSP00000512521.1
C5	ENST00000867873.1		c.4311A>C	p.Glu1437Asp	missense	Exon 34 of 40	ENSP00000537932.1

Frequencies

GnomAD3 genomes

AF:

0.0454

AC:

6910

AN:

152210

Hom.:

230

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0188

Gnomad AMI

AF:

0.0307

Gnomad AMR

AF:

0.0547

Gnomad ASJ

AF:

0.0629

Gnomad EAS

AF:

0.00115

Gnomad SAS

AF:

0.0741

Gnomad FIN

AF:

0.0132

Gnomad MID

AF:

0.0918

Gnomad NFE

AF:

0.0649

Gnomad OTH

AF:

0.0478

GnomAD2 exomes

AF:

0.0537

AC:

13490

AN:

251280

AF XY:

0.0547

show subpopulations

Gnomad AFR exome

AF:

0.0191

Gnomad AMR exome

AF:

0.0578

Gnomad ASJ exome

AF:

0.0646

Gnomad EAS exome

AF:

0.000870

Gnomad FIN exome

AF:

0.0152

Gnomad NFE exome

AF:

0.0685

Gnomad OTH exome

AF:

0.0570

GnomAD4 exome

AF:

0.0626

AC:

91337

AN:

1458310

Hom.:

3253

Cov.:

AF XY:

0.0630

AC XY:

45745

AN XY:

725660

show subpopulations

African (AFR)

AF:

0.0181

AC:

605

AN:

33420

American (AMR)

AF:

0.0566

AC:

2532

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.0618

AC:

1613

AN:

26108

East Asian (EAS)

AF:

0.000731

AC:

AN:

39674

South Asian (SAS)

AF:

0.0673

AC:

5796

AN:

86146

European-Finnish (FIN)

AF:

0.0168

AC:

896

AN:

53400

Middle Eastern (MID)

AF:

0.0613

AC:

353

AN:

5760

European-Non Finnish (NFE)

AF:

0.0685

AC:

75917

AN:

1108818

Other (OTH)

AF:

0.0597

AC:

3596

AN:

60274

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

3738

7476

11213

14951

18689

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2820

5640

8460

11280

14100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0453

AC:

6906

AN:

152328

Hom.:

230

Cov.:

AF XY:

0.0430

AC XY:

3202

AN XY:

74490

show subpopulations

African (AFR)

AF:

0.0189

AC:

784

AN:

41568

American (AMR)

AF:

0.0545

AC:

834

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.0629

AC:

218

AN:

3468

East Asian (EAS)

AF:

0.00116

AC:

AN:

5192

South Asian (SAS)

AF:

0.0735

AC:

355

AN:

4830

European-Finnish (FIN)

AF:

0.0132

AC:

140

AN:

10616

Middle Eastern (MID)

AF:

0.0918

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0649

AC:

4414

AN:

68034

Other (OTH)

AF:

0.0473

AC:

100

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

337

675

1012

1350

1687

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

160

240

320

400

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0615

Hom.:

932

Bravo

AF:

0.0472

TwinsUK

AF:

0.0739

AC:

274

ALSPAC

AF:

0.0667

AC:

257

ESP6500AA

AF:

0.0229

AC:

101

ESP6500EA

AF:

0.0698

AC:

600

ExAC

AF:

0.0549

AC:

6662

Asia WGS

AF:

0.0340

AC:

118

AN:

3478

EpiCase

AF:

0.0701

EpiControl

AF:

0.0711

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.069

BayesDel_addAF

Benign

-0.72

BayesDel_noAF

Benign

-0.76

CADD

Benign

5.4

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.079

Eigen

Benign

-0.89

Eigen_PC

Benign

-0.80

FATHMM_MKL

Benign

0.58

LIST_S2

Benign

0.52

MetaRNN

Benign

0.0018

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.2

PhyloP100

-0.21

PrimateAI

Benign

0.36

PROVEAN

Benign

-1.1

REVEL

Benign

0.073

Sift

Benign

0.14

Sift4G

Benign

0.43

Polyphen

0.0020

Vest4

0.062

MutPred

0.26

Loss of ubiquitination at K1440 (P = 0.1741)

MPC

0.16

ClinPred

0.0035

GERP RS

-2.9

Varity_R

0.38

gMVP

0.53

Mutation Taster

=86/14

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over