Genetic Variant C5:c.4017+17C>G (chr9-120974762-G-C) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001735.3(C5):c.4017+17C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.208 in 1,602,582 control chromosomes in the GnomAD database, including 41,761 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.30 ( 9148 hom., cov: 32)

Exomes 𝑓: 0.20 ( 32613 hom. )

Consequence

C5
NM_001735.3 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.465

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.85).

BP6

Variant 9-120974762-G-C is Benign according to our data. Variant chr9-120974762-G-C is described in ClinVar as [Benign]. Clinvar id is 1166860.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-120974762-G-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.575 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
C5	NM_001735.3 link	c.4017+17C>G		intron_variant	Intron 30 of 40	ENST00000223642.3	NP_001726.2	P01031
C5	NM_001317163.2 link	c.4035+17C>G		intron_variant	Intron 30 of 40		NP_001304092.1	P01031A0A8Q3SID6Q59GS8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
C5	ENST00000223642.3 link	c.4017+17C>G		intron_variant	Intron 30 of 40	1	NM_001735.3	ENSP00000223642.1		P01031

Frequencies

GnomAD3 genomes

AF:

0.296

AC:

44933

AN:

151936

Hom.:

9119

Cov.:

show subpopulations

Gnomad AFR

AF:

0.581

Gnomad AMI

AF:

0.267

Gnomad AMR

AF:

0.171

Gnomad ASJ

AF:

0.130

Gnomad EAS

AF:

0.244

Gnomad SAS

AF:

0.135

Gnomad FIN

AF:

0.155

Gnomad MID

AF:

0.133

Gnomad NFE

AF:

0.199

Gnomad OTH

AF:

0.239

GnomAD3 exomes

AF:

0.203

AC:

50935

AN:

251358

Hom.:

6903

AF XY:

0.193

AC XY:

26250

AN XY:

135868

show subpopulations

Gnomad AFR exome

AF:

0.600

Gnomad AMR exome

AF:

0.126

Gnomad ASJ exome

AF:

0.132

Gnomad EAS exome

AF:

0.237

Gnomad SAS exome

AF:

0.124

Gnomad FIN exome

AF:

0.160

Gnomad NFE exome

AF:

0.200

Gnomad OTH exome

AF:

0.179

GnomAD4 exome

AF:

0.198

AC:

287559

AN:

1450528

Hom.:

32613

Cov.:

AF XY:

0.195

AC XY:

140863

AN XY:

722452

show subpopulations

Gnomad4 AFR exome

AF:

0.600

Gnomad4 AMR exome

AF:

0.132

Gnomad4 ASJ exome

AF:

0.133

Gnomad4 EAS exome

AF:

0.245

Gnomad4 SAS exome

AF:

0.124

Gnomad4 FIN exome

AF:

0.165

Gnomad4 NFE exome

AF:

0.196

Gnomad4 OTH exome

AF:

0.207

GnomAD4 genome

AF:

0.296

AC:

45011

AN:

152054

Hom.:

9148

Cov.:

AF XY:

0.288

AC XY:

21395

AN XY:

74352

show subpopulations

Gnomad4 AFR

AF:

0.582

Gnomad4 AMR

AF:

0.170

Gnomad4 ASJ

AF:

0.130

Gnomad4 EAS

AF:

0.243

Gnomad4 SAS

AF:

0.133

Gnomad4 FIN

AF:

0.155

Gnomad4 NFE

AF:

0.199

Gnomad4 OTH

AF:

0.239

Alfa

AF:

0.230

Hom.:

1034

Bravo

AF:

0.310

Asia WGS

AF:

0.227

AC:

789

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: 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

-0.85

CADD

Benign

1.7

DANN

Benign

0.36

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over