rs2269066

Variant names:

• chr9-120974740-C-T
• rs2269066
• NM_001735.3:c.4017+39G>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.4017+39G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.109 in 1,550,100 control chromosomes in the GnomAD database, including 11,916 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 0.17 (2975 hom., cov: 32)
  • Exomes 𝑓: 0.10 (8941 hom.)
• Consequence: C5 NM_001735.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.132
• Publications: 26 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=-0.81).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.32 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
C5	NM_001735.3	c.4017+39G>A		intron_variant	Intron 30 of 40	ENST00000223642.3	NP_001726.2
C5	NM_001317163.2	c.4035+39G>A		intron_variant	Intron 30 of 40		NP_001304092.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
C5	ENST00000223642.3	c.4017+39G>A		intron_variant	Intron 30 of 40	1	NM_001735.3	ENSP00000223642.1

Frequencies

GnomAD3 genomes AF: 0.166 AC: 25315 AN: 152102 Hom.: 2970 Cov.: 32

Gnomad AFR AF: 0.325

Gnomad AMI AF: 0.234

Gnomad AMR AF: 0.0863

Gnomad ASJ AF: 0.0715

Gnomad EAS AF: 0.212

Gnomad SAS AF: 0.0474

Gnomad FIN AF: 0.109

Gnomad MID AF: 0.0570

Gnomad NFE AF: 0.107

Gnomad OTH AF: 0.141

GnomAD2 exomes AF: 0.112 AC: 28263 AN: 251228 AF XY: 0.107

Gnomad AFR exome AF: 0.338

Gnomad AMR exome AF: 0.0532

Gnomad ASJ exome AF: 0.0689

Gnomad EAS exome AF: 0.202

Gnomad FIN exome AF: 0.115

Gnomad NFE exome AF: 0.106

Gnomad OTH exome AF: 0.102

GnomAD4 exome AF: 0.103 AC: 143775 AN: 1397880 Hom.: 8941 Cov.: 25 AF XY: 0.101 AC XY: 70580 AN XY: 699534

African (AFR) AF: 0.331 AC: 10305 AN: 31176

American (AMR) AF: 0.0580 AC: 2589 AN: 44658

Ashkenazi Jewish (ASJ) AF: 0.0705 AC: 1816 AN: 25776

East Asian (EAS) AF: 0.216 AC: 8521 AN: 39372

South Asian (SAS) AF: 0.0448 AC: 3808 AN: 85088

European-Finnish (FIN) AF: 0.115 AC: 6153 AN: 53352

Middle Eastern (MID) AF: 0.0736 AC: 416 AN: 5652

European-Non Finnish (NFE) AF: 0.0983 AC: 103661 AN: 1054578

Other (OTH) AF: 0.112 AC: 6506 AN: 58228

GnomAD4 genome AF: 0.167 AC: 25361 AN: 152220 Hom.: 2975 Cov.: 32 AF XY: 0.162 AC XY: 12056 AN XY: 74442

African (AFR) AF: 0.325 AC: 13485 AN: 41496

American (AMR) AF: 0.0862 AC: 1318 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0715 AC: 248 AN: 3468

East Asian (EAS) AF: 0.212 AC: 1098 AN: 5180

South Asian (SAS) AF: 0.0460 AC: 222 AN: 4828

European-Finnish (FIN) AF: 0.109 AC: 1160 AN: 10612

Middle Eastern (MID) AF: 0.0612 AC: 18 AN: 294

European-Non Finnish (NFE) AF: 0.107 AC: 7301 AN: 68020

Other (OTH) AF: 0.141 AC: 298 AN: 2116

Alfa AF: 0.116 Hom.: 2286

Bravo AF: 0.173

Asia WGS AF: 0.160 AC: 557 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	4.8
DANN	Benign	0.41
PhyloP100		0.13
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: rs2269066; hg19: chr9-123737018; COSMIC: COSV107302672; COSMIC: COSV107302672;