5-39341276-G-C

Variant names:

• chr5-39341276-G-C
• rs121909592
• NM_001737.5:c.346C>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001737.5(C9):​c.346C>G​(p.Arg116Gly) 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. 13/22 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. R116Q) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: C9 NM_001737.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0690
• Publications: 0 publications found

Genes affected

C9 (HGNC:1358): (complement C9) This gene encodes the final component of the complement system. It participates in the formation of the Membrane Attack Complex (MAC). The MAC assembles on bacterial membranes to form a pore, permitting disruption of bacterial membrane organization. Mutations in this gene cause component C9 deficiency. [provided by RefSeq, Feb 2009]

C9 Gene-Disease associations (from GenCC):

• complement component 9 deficiency

  Inheritance: Unknown, AR Classification: STRONG, MODERATE Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), Ambry Genetics

ENSG00000289699 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.4054954).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001737.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C9	NM_001737.5	MANE Select	c.346C>G	p.Arg116Gly	missense	Exon 4 of 11	NP_001728.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C9	ENST00000263408.5	TSL:1 MANE Select	c.346C>G	p.Arg116Gly	missense	Exon 4 of 11	ENSP00000263408.4
	C9	ENST00000509186.6	TSL:3	c.274C>G	p.Arg92Gly	missense	Exon 4 of 11	ENSP00000512235.1
	C9	ENST00000695880.1		c.346C>G	p.Arg116Gly	missense	Exon 4 of 10	ENSP00000512236.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	0.0063	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.60	D
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.46
FATHMM_MKL	Benign	0.072	N
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.061	D
MetaRNN	Benign	0.41	T
MetaSVM	Benign	-0.32	T
MutationAssessor	Benign	1.2	L
PhyloP100		0.069
PrimateAI	Benign	0.31	T
PROVEAN	Pathogenic	-5.9	D
REVEL	Uncertain	0.30
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.013	D
Polyphen		1.0	D
Vest4		0.40
MutPred		0.45		Loss of MoRF binding (P = 0.068)
MVP		0.71
MPC		0.27
ClinPred		0.98	D
GERP RS		2.1
Varity_R		0.39
gMVP		0.80
Mutation Taster		=81/19	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

Other links and lift over

dbSNP: rs121909592; hg19: chr5-39341378;