chr9-120953825-T-G

Variant names:

• chr9-120953825-T-G
• rs41258306
• NM_001735.3:c.4806A>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_001735.3(C5):​c.4806A>C​(p.Lys1602Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000109 in 1,461,278 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. K1602K) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: C5 NM_001735.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0580

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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
C5	NM_001735.3	c.4806A>C	p.Lys1602Asn	missense_variant	Exon 40 of 41	ENST00000223642.3	NP_001726.2
C5	NM_001317163.2	c.4824A>C	p.Lys1608Asn	missense_variant	Exon 40 of 41		NP_001304092.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
C5	ENST00000223642.3	c.4806A>C	p.Lys1602Asn	missense_variant	Exon 40 of 41	1	NM_001735.3	ENSP00000223642.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000109 AC: 16 AN: 1461278 Hom.: 0 Cov.: 31 AF XY: 0.0000165 AC XY: 12 AN XY: 726968

Gnomad4 AFR exome AF: 0.00 AC: 0 AN: 33462

Gnomad4 AMR exome AF: 0.00 AC: 0 AN: 44724

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 26132

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 39684

Gnomad4 SAS exome AF: 0.00 AC: 0 AN: 86250

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 53418

Gnomad4 NFE exome AF: 0.0000144 AC: 16 AN: 1111460

Gnomad4 Remaining exome AF: 0.00 AC: 0 AN: 60380

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.72
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.16	T
Eigen	Benign	0.090
Eigen_PC	Benign	-0.046
FATHMM_MKL	Benign	0.53	D
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.081	D
MetaRNN	Uncertain	0.72	D
MetaSVM	Uncertain	-0.28	T
MutationAssessor	Pathogenic	3.4	M
PrimateAI	Benign	0.42	T
PROVEAN	Uncertain	-2.4	N
REVEL	Uncertain	0.30
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0080	D
Polyphen		1.0	D
Vest4		0.46
MutPred		0.70		Loss of ubiquitination at K1602 (P = 0.0218);
MVP		0.77
MPC		0.68
ClinPred		0.98	D
GERP RS		0.60
Varity_R		0.61
gMVP		0.82
Mutation Taster		=59/41	polymorphism

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: rs41258306; hg19: chr9-123716103;