9-121046685-C-A

Variant names:

• chr9-121046685-C-A
• rs2300934
• NM_001735.3:c.66-302G>T

Variant summary

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

The NM_001735.3(C5):​c.66-302G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.355 in 151,968 control chromosomes in the GnomAD database, including 11,898 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 0.36 (11898 hom., cov: 32)
• Consequence: C5 NM_001735.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0420
• Publications: 8 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=-0.82).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.593 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
C5	NM_001735.3	c.66-302G>T		intron_variant	Intron 1 of 40	ENST00000223642.3	NP_001726.2
C5	NM_001317163.2	c.84-302G>T		intron_variant	Intron 1 of 40		NP_001304092.1
C5	NM_001317164.2	c.66-302G>T		intron_variant	Intron 1 of 20		NP_001304093.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
C5	ENST00000223642.3	c.66-302G>T		intron_variant	Intron 1 of 40	1	NM_001735.3	ENSP00000223642.1

Frequencies

GnomAD3 genomes AF: 0.356 AC: 54005 AN: 151850 Hom.: 11885 Cov.: 32

Gnomad AFR AF: 0.0837

Gnomad AMI AF: 0.644

Gnomad AMR AF: 0.485

Gnomad ASJ AF: 0.493

Gnomad EAS AF: 0.551

Gnomad SAS AF: 0.610

Gnomad FIN AF: 0.506

Gnomad MID AF: 0.472

Gnomad NFE AF: 0.423

Gnomad OTH AF: 0.400

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

GnomAD4 genome AF: 0.355 AC: 54017 AN: 151968 Hom.: 11898 Cov.: 32 AF XY: 0.366 AC XY: 27168 AN XY: 74272

African (AFR) AF: 0.0834 AC: 3460 AN: 41484

American (AMR) AF: 0.486 AC: 7407 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.493 AC: 1712 AN: 3470

East Asian (EAS) AF: 0.552 AC: 2846 AN: 5158

South Asian (SAS) AF: 0.611 AC: 2938 AN: 4806

European-Finnish (FIN) AF: 0.506 AC: 5339 AN: 10554

Middle Eastern (MID) AF: 0.463 AC: 136 AN: 294

European-Non Finnish (NFE) AF: 0.423 AC: 28744 AN: 67928

Other (OTH) AF: 0.402 AC: 848 AN: 2112

Alfa AF: 0.359 Hom.: 2259

Bravo AF: 0.342

Asia WGS AF: 0.518 AC: 1800 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	13
DANN	Benign	0.73
PhyloP100		0.042
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: rs2300934; hg19: chr9-123808963; COSMIC: COSV56325493;