dbSNP rs12235400: C5:c.4220+650G>A (chr9-120968411-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001735.3(C5):c.4220+650G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0704 in 152,228 control chromosomes in the GnomAD database, including 869 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.070 ( 869 hom., cov: 32)

Consequence

C5
NM_001735.3 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.102

Publications

6 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 -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.9).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.183 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
C5	NM_001735.3 link	c.4220+650G>A		intron_variant	Intron 33 of 40	ENST00000223642.3	NP_001726.2
C5	NM_001317163.2 link	c.4238+650G>A		intron_variant	Intron 33 of 40		NP_001304092.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
C5	ENST00000223642.3 link	c.4220+650G>A		intron_variant	Intron 33 of 40	1	NM_001735.3	ENSP00000223642.1

Frequencies

GnomAD3 genomes

AF:

0.0702

AC:

10684

AN:

152110

Hom.:

865

Cov.:

show subpopulations

Gnomad AFR

AF:

0.182

Gnomad AMI

AF:

0.00329

Gnomad AMR

AF:

0.0315

Gnomad ASJ

AF:

0.0176

Gnomad EAS

AF:

0.193

Gnomad SAS

AF:

0.0441

Gnomad FIN

AF:

0.0214

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.0155

Gnomad OTH

AF:

0.0578

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.0704

AC:

10712

AN:

152228

Hom.:

869

Cov.:

AF XY:

0.0702

AC XY:

5227

AN XY:

74440

show subpopulations

African (AFR)

AF:

0.182

AC:

7552

AN:

41500

American (AMR)

AF:

0.0314

AC:

481

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.0176

AC:

AN:

3472

East Asian (EAS)

AF:

0.193

AC:

999

AN:

5180

South Asian (SAS)

AF:

0.0433

AC:

209

AN:

4826

European-Finnish (FIN)

AF:

0.0214

AC:

227

AN:

10616

Middle Eastern (MID)

AF:

0.0238

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0155

AC:

1053

AN:

68016

Other (OTH)

AF:

0.0568

AC:

120

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

462

924

1385

1847

2309

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

116

232

348

464

580

<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:

0.0315

Hom.:

152

Bravo

AF:

0.0755

Asia WGS

AF:

0.112

AC:

389

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

5.7

(source)

DANN

Benign

0.61

PhyloP100

-0.10

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over