chr9-121020778-T-G

Variant names:

• chr9-121020778-T-G
• rs2159777
• NM_001735.3:c.1303-599A>C

Variant summary

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

The NM_001317163.2(C5):​c.1321-599A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.525 in 152,080 control chromosomes in the GnomAD database, including 21,269 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 (21269 hom., cov: 32)
• Consequence: C5 NM_001317163.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.721
• Publications: 7 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=-0.84).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.762 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001317163.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C5	NM_001735.3	MANE Select	c.1303-599A>C		intron	N/A	NP_001726.2
	C5	NM_001317163.2		c.1321-599A>C		intron	N/A	NP_001304092.1
	C5	NM_001317164.2		c.1303-599A>C		intron	N/A	NP_001304093.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C5	ENST00000223642.3	TSL:1 MANE Select	c.1303-599A>C		intron	N/A	ENSP00000223642.1
	C5	ENST00000696281.1		c.1321-599A>C		intron	N/A	ENSP00000512521.1
	C5	ENST00000867873.1		c.1303-599A>C		intron	N/A	ENSP00000537932.1

Frequencies

GnomAD3 genomes AF: 0.525 AC: 79708 AN: 151962 Hom.: 21240 Cov.: 32

Gnomad AFR AF: 0.461

Gnomad AMI AF: 0.669

Gnomad AMR AF: 0.564

Gnomad ASJ AF: 0.577

Gnomad EAS AF: 0.782

Gnomad SAS AF: 0.667

Gnomad FIN AF: 0.578

Gnomad MID AF: 0.509

Gnomad NFE AF: 0.511

Gnomad OTH AF: 0.536

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

GnomAD4 genome AF: 0.525 AC: 79790 AN: 152080 Hom.: 21269 Cov.: 32 AF XY: 0.530 AC XY: 39392 AN XY: 74334

African (AFR) AF: 0.462 AC: 19149 AN: 41468

American (AMR) AF: 0.564 AC: 8624 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.577 AC: 2003 AN: 3472

East Asian (EAS) AF: 0.782 AC: 4047 AN: 5176

South Asian (SAS) AF: 0.667 AC: 3217 AN: 4822

European-Finnish (FIN) AF: 0.578 AC: 6103 AN: 10562

Middle Eastern (MID) AF: 0.503 AC: 148 AN: 294

European-Non Finnish (NFE) AF: 0.511 AC: 34750 AN: 67976

Other (OTH) AF: 0.539 AC: 1139 AN: 2114

Alfa AF: 0.451 Hom.: 2420

Bravo AF: 0.520

Asia WGS AF: 0.697 AC: 2424 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	10
DANN	Benign	0.42
PhyloP100		0.72
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: rs2159777; hg19: chr9-123783056;