rs2269066

chr9-120974740-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001735.3(C5):c.4017+39G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.109 in 1,550,100 control chromosomes in the GnomAD database, including 11,916 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 0.17 (2975 hom., cov: 32)
  • Exomes 𝑓: 0.10 (8941 hom.)
• Consequence: C5 NM_001735.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.132

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.32 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
C5	NM_001735.3	c.4017+39G>A		intron_variant		ENST00000223642.3
C5	NM_001317163.2	c.4035+39G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
C5	ENST00000223642.3	c.4017+39G>A		intron_variant		1	NM_001735.3	P1

Frequencies

GnomAD3 genomes AF: 0.166 AC: 25315 AN: 152102 Hom.: 2970 Cov.: 32

Gnomad AFR AF: 0.325

Gnomad AMI AF: 0.234

Gnomad AMR AF: 0.0863

Gnomad ASJ AF: 0.0715

Gnomad EAS AF: 0.212

Gnomad SAS AF: 0.0474

Gnomad FIN AF: 0.109

Gnomad MID AF: 0.0570

Gnomad NFE AF: 0.107

Gnomad OTH AF: 0.141

GnomAD3 exomes AF: 0.112 AC: 28263 AN: 251228 Hom.: 2296 AF XY: 0.107 AC XY: 14470 AN XY: 135822

Gnomad AFR exome AF: 0.338

Gnomad AMR exome AF: 0.0532

Gnomad ASJ exome AF: 0.0689

Gnomad EAS exome AF: 0.202

Gnomad SAS exome AF: 0.0445

Gnomad FIN exome AF: 0.115

Gnomad NFE exome AF: 0.106

Gnomad OTH exome AF: 0.102

GnomAD4 exome AF: 0.103 AC: 143775 AN: 1397880 Hom.: 8941 Cov.: 25 AF XY: 0.101 AC XY: 70580 AN XY: 699534

Gnomad4 AFR exome AF: 0.331

Gnomad4 AMR exome AF: 0.0580

Gnomad4 ASJ exome AF: 0.0705

Gnomad4 EAS exome AF: 0.216

Gnomad4 SAS exome AF: 0.0448

Gnomad4 FIN exome AF: 0.115

Gnomad4 NFE exome AF: 0.0983

Gnomad4 OTH exome AF: 0.112

GnomAD4 genome AF: 0.167 AC: 25361 AN: 152220 Hom.: 2975 Cov.: 32 AF XY: 0.162 AC XY: 12056 AN XY: 74442

Gnomad4 AFR AF: 0.325

Gnomad4 AMR AF: 0.0862

Gnomad4 ASJ AF: 0.0715

Gnomad4 EAS AF: 0.212

Gnomad4 SAS AF: 0.0460

Gnomad4 FIN AF: 0.109

Gnomad4 NFE AF: 0.107

Gnomad4 OTH AF: 0.141

Alfa AF: 0.110 Hom.: 1602

Bravo AF: 0.173

Asia WGS AF: 0.160 AC: 557 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
Cadd	Benign	4.8
Dann	Benign	0.41

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

LitVar

Other links and lift over

dbSNP: rs2269066; hg19: chr9-123737018;