rs992670

Positions:

• chr9-121019492-G-A
• chr9-121019492-G-T

Variant summary

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

The NM_001735.3(C5):​c.1506+484C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.524 in 152,008 control chromosomes in the GnomAD database, including 21,103 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 0.52 (21103 hom., cov: 32)
• Consequence: C5 NM_001735.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.330

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=-0.9).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.726 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
C5	NM_001735.3	c.1506+484C>T		intron_variant		ENST00000223642.3
C5	NM_001317163.2	c.1524+484C>T		intron_variant
C5	NM_001317164.2	c.1506+484C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
C5	ENST00000223642.3	c.1506+484C>T		intron_variant		1	NM_001735.3	P1

Frequencies

GnomAD3 genomes AF: 0.523 AC: 79503 AN: 151888 Hom.: 21075 Cov.: 32

Gnomad AFR AF: 0.462

Gnomad AMI AF: 0.671

Gnomad AMR AF: 0.563

Gnomad ASJ AF: 0.576

Gnomad EAS AF: 0.745

Gnomad SAS AF: 0.659

Gnomad FIN AF: 0.581

Gnomad MID AF: 0.509

Gnomad NFE AF: 0.512

Gnomad OTH AF: 0.534

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

GnomAD4 genome AF: 0.524 AC: 79585 AN: 152008 Hom.: 21103 Cov.: 32 AF XY: 0.529 AC XY: 39270 AN XY: 74290

Gnomad4 AFR AF: 0.462

Gnomad4 AMR AF: 0.564

Gnomad4 ASJ AF: 0.576

Gnomad4 EAS AF: 0.745

Gnomad4 SAS AF: 0.660

Gnomad4 FIN AF: 0.581

Gnomad4 NFE AF: 0.512

Gnomad4 OTH AF: 0.535

Alfa AF: 0.522 Hom.: 4086

Bravo AF: 0.519

Asia WGS AF: 0.665 AC: 2314 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	0.83
DANN	Benign	0.48

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: rs992670; hg19: chr9-123781770; COSMIC: COSV56325446;