9-121027356-C-T

Position:

• chr9-121027356-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.759-82G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.451 in 780,274 control chromosomes in the GnomAD database, including 84,505 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 0.38 (12725 hom., cov: 32)
  • Exomes 𝑓: 0.47 (71780 hom.)
• Consequence: C5 NM_001735.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.131

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.612 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
C5	NM_001735.3	c.759-82G>A		intron_variant		ENST00000223642.3	NP_001726.2
C5	NM_001317163.2	c.777-82G>A		intron_variant			NP_001304092.1
C5	NM_001317164.2	c.759-82G>A		intron_variant			NP_001304093.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
C5	ENST00000223642.3	c.759-82G>A		intron_variant		1	NM_001735.3	ENSP00000223642.1

Frequencies

GnomAD3 genomes AF: 0.377 AC: 57211 AN: 151932 Hom.: 12711 Cov.: 32

Gnomad AFR AF: 0.129

Gnomad AMI AF: 0.643

Gnomad AMR AF: 0.494

Gnomad ASJ AF: 0.521

Gnomad EAS AF: 0.561

Gnomad SAS AF: 0.629

Gnomad FIN AF: 0.510

Gnomad MID AF: 0.484

Gnomad NFE AF: 0.435

Gnomad OTH AF: 0.415

GnomAD4 exome AF: 0.469 AC: 294599 AN: 628220 Hom.: 71780 AF XY: 0.479 AC XY: 160932 AN XY: 335858

Gnomad4 AFR exome AF: 0.129

Gnomad4 AMR exome AF: 0.542

Gnomad4 ASJ exome AF: 0.512

Gnomad4 EAS exome AF: 0.529

Gnomad4 SAS exome AF: 0.635

Gnomad4 FIN exome AF: 0.484

Gnomad4 NFE exome AF: 0.442

Gnomad4 OTH exome AF: 0.450

GnomAD4 genome AF: 0.376 AC: 57238 AN: 152054 Hom.: 12725 Cov.: 32 AF XY: 0.387 AC XY: 28733 AN XY: 74330

Gnomad4 AFR AF: 0.129

Gnomad4 AMR AF: 0.495

Gnomad4 ASJ AF: 0.521

Gnomad4 EAS AF: 0.561

Gnomad4 SAS AF: 0.630

Gnomad4 FIN AF: 0.510

Gnomad4 NFE AF: 0.435

Gnomad4 OTH AF: 0.416

Alfa AF: 0.339 Hom.: 1882

Bravo AF: 0.364

Asia WGS AF: 0.532 AC: 1849 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	5.7
DANN	Benign	0.67

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: rs2416811; hg19: chr9-123789634; COSMIC: COSV56325480;