9-120993882-C-T

Variant names:

• chr9-120993882-C-T
• rs2159776
• NM_001735.3:c.2851+2358G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001735.3(C5):​c.2851+2358G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.51 in 151,854 control chromosomes in the GnomAD database, including 20,223 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 0.51 (20223 hom., cov: 31)
• Consequence: C5 NM_001735.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.101
• Publications: 14 publications found

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 Gene-Disease associations (from GenCC):

• complement component 5 deficiency

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.99).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.699 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
C5	NM_001735.3	c.2851+2358G>A		intron_variant	Intron 22 of 40	ENST00000223642.3	NP_001726.2
C5	NM_001317163.2	c.2869+2358G>A		intron_variant	Intron 22 of 40		NP_001304092.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
C5	ENST00000223642.3	c.2851+2358G>A		intron_variant	Intron 22 of 40	1	NM_001735.3	ENSP00000223642.1

Frequencies

GnomAD3 genomes AF: 0.510 AC: 77351 AN: 151736 Hom.: 20208 Cov.: 31

Gnomad AFR AF: 0.383

Gnomad AMI AF: 0.681

Gnomad AMR AF: 0.581

Gnomad ASJ AF: 0.572

Gnomad EAS AF: 0.593

Gnomad SAS AF: 0.718

Gnomad FIN AF: 0.576

Gnomad MID AF: 0.574

Gnomad NFE AF: 0.533

Gnomad OTH AF: 0.519

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

GnomAD4 genome AF: 0.510 AC: 77392 AN: 151854 Hom.: 20223 Cov.: 31 AF XY: 0.517 AC XY: 38358 AN XY: 74226

African (AFR) AF: 0.383 AC: 15820 AN: 41338

American (AMR) AF: 0.582 AC: 8878 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.572 AC: 1982 AN: 3466

East Asian (EAS) AF: 0.593 AC: 3063 AN: 5164

South Asian (SAS) AF: 0.719 AC: 3470 AN: 4826

European-Finnish (FIN) AF: 0.576 AC: 6072 AN: 10534

Middle Eastern (MID) AF: 0.576 AC: 167 AN: 290

European-Non Finnish (NFE) AF: 0.533 AC: 36225 AN: 67952

Other (OTH) AF: 0.520 AC: 1098 AN: 2112

Alfa AF: 0.505 Hom.: 3304

Bravo AF: 0.503

Asia WGS AF: 0.602 AC: 2094 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	1.8
DANN	Benign	0.51
PhyloP100		-0.10
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2159776; hg19: chr9-123756160;