rs56040400

chr9-120997683-C-Gchr9-120997683-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PM2 PM5 BP4_Strong

The NM_001735.3(C5):c.2654G>C(p.Arg885Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R885C) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: C5 NM_001735.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.69

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr9-120997683-C-T is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.058204383).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
C5	NM_001735.3	c.2654G>C	p.Arg885Pro	missense_variant	21/41	ENST00000223642.3
C5	NM_001317163.2	c.2672G>C	p.Arg891Pro	missense_variant	21/41

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
C5	ENST00000223642.3	c.2654G>C	p.Arg885Pro	missense_variant	21/41	1	NM_001735.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.68
Cadd	Benign	0.028
Dann	Benign	0.52
DEOGEN2	Benign	0.15	T
Eigen	Benign	-2.3
Eigen_PC	Benign	-2.4
FATHMM_MKL	Benign	0.0060	N
LIST_S2	Benign	0.32	T
M_CAP	Benign	0.0041	T
MetaRNN	Benign	0.058	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.0	L
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.044
Sift	Benign	0.21	T
Sift4G	Benign	0.20	T
Polyphen		0.0	B
Vest4		0.10
MutPred		0.43		Loss of sheet (P = 0.0025);
MVP		0.18
MPC		0.22
ClinPred		0.098	T
GERP RS		-11
Varity_R		0.57
gMVP		0.74

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: rs56040400; hg19: chr9-123759961;