rs12685344

Positions:

• chr9-121002713-G-A
• chr9-121002713-G-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001735.3(C5):​c.2562+3206C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0799 in 151,978 control chromosomes in the GnomAD database, including 521 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 0.080 (521 hom., cov: 30)
• Consequence: C5 NM_001735.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.365

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0929 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
C5	NM_001735.3	c.2562+3206C>T		intron_variant		ENST00000223642.3	NP_001726.2
C5	NM_001317163.2	c.2580+3206C>T		intron_variant			NP_001304092.1
C5	NM_001317164.2	c.2563-2662C>T		intron_variant			NP_001304093.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
C5	ENST00000223642.3	c.2562+3206C>T		intron_variant		1	NM_001735.3	ENSP00000223642	P1

Frequencies

GnomAD3 genomes AF: 0.0799 AC: 12136 AN: 151860 Hom.: 522 Cov.: 30

Gnomad AFR AF: 0.0770

Gnomad AMI AF: 0.0352

Gnomad AMR AF: 0.0670

Gnomad ASJ AF: 0.0565

Gnomad EAS AF: 0.0313

Gnomad SAS AF: 0.0886

Gnomad FIN AF: 0.0490

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.0948

Gnomad OTH AF: 0.0647

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

GnomAD4 genome AF: 0.0799 AC: 12140 AN: 151978 Hom.: 521 Cov.: 30 AF XY: 0.0771 AC XY: 5726 AN XY: 74306

Gnomad4 AFR AF: 0.0769

Gnomad4 AMR AF: 0.0668

Gnomad4 ASJ AF: 0.0565

Gnomad4 EAS AF: 0.0310

Gnomad4 SAS AF: 0.0885

Gnomad4 FIN AF: 0.0490

Gnomad4 NFE AF: 0.0948

Gnomad4 OTH AF: 0.0649

Alfa AF: 0.0827 Hom.: 345

Bravo AF: 0.0809

Asia WGS AF: 0.0610 AC: 212 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	1.6
DANN	Benign	0.30

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: rs12685344; hg19: chr9-123764991;