9-121015870-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.1996+384G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.522 in 151,912 control chromosomes in the GnomAD database, including 20,964 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 (20964 hom., cov: 31)
• Consequence: C5 NM_001735.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.808

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=-0.87).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.724 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
C5	NM_001735.3	c.1996+384G>A		intron_variant		ENST00000223642.3
C5	NM_001317163.2	c.2014+384G>A		intron_variant
C5	NM_001317164.2	c.1996+384G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
C5	ENST00000223642.3	c.1996+384G>A		intron_variant		1	NM_001735.3	P1

Frequencies

GnomAD3 genomes AF: 0.522 AC: 79217 AN: 151794 Hom.: 20938 Cov.: 31

Gnomad AFR AF: 0.460

Gnomad AMI AF: 0.669

Gnomad AMR AF: 0.559

Gnomad ASJ AF: 0.576

Gnomad EAS AF: 0.743

Gnomad SAS AF: 0.659

Gnomad FIN AF: 0.578

Gnomad MID AF: 0.509

Gnomad NFE AF: 0.511

Gnomad OTH AF: 0.534

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

GnomAD4 genome AF: 0.522 AC: 79295 AN: 151912 Hom.: 20964 Cov.: 31 AF XY: 0.527 AC XY: 39103 AN XY: 74222

Gnomad4 AFR AF: 0.461

Gnomad4 AMR AF: 0.560

Gnomad4 ASJ AF: 0.576

Gnomad4 EAS AF: 0.744

Gnomad4 SAS AF: 0.660

Gnomad4 FIN AF: 0.578

Gnomad4 NFE AF: 0.511

Gnomad4 OTH AF: 0.534

Alfa AF: 0.523 Hom.: 17337

Bravo AF: 0.518

Asia WGS AF: 0.663 AC: 2306 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
Cadd	Benign	1.0
Dann	Benign	0.69

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: rs10116271; hg19: chr9-123778148; COSMIC: COSV56325423;