rs2269067

chr9-120974762-G-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

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
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.465

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]

ACMG classification

Verdict is Benign. Variant got -14 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_single_submitter, 1 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/exons	MANE	UniProt
C5	NM_001735.3	c.4017+17C>G		intron_variant		ENST00000223642.3
C5	NM_001317163.2	c.4035+17C>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
C5	ENST00000223642.3	c.4017+17C>G		intron_variant		1	NM_001735.3	P1

Frequencies

GnomAD3 genomes AF: 0.296 AC: 44933 AN: 151936 Hom.: 9119 Cov.: 32

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

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.: 30 AF XY: 0.195 AC XY: 140863 AN XY: 722452

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.: 32 AF XY: 0.288 AC XY: 21395 AN XY: 74352

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:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

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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

Other links and lift over

dbSNP: rs2269067; hg19: chr9-123737040; COSMIC: COSV56326625; COSMIC: COSV56326625;