rs121909593

Positions:

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PP3_StrongPP5

The NM_001737.5(C9):c.355T>G(p.Cys119Gly) variant causes a missense change. The variant allele was found at a frequency of 0.000189 in 1,614,010 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00019 ( 0 hom. )

Consequence

C9
NM_001737.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:2

Conservation

PhyloP100: 6.27

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.963

PP5

Variant 5-39341267-A-C is Pathogenic according to our data. Variant chr5-39341267-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 17042.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
C9	NM_001737.5 linkuse as main transcript	c.355T>G	p.Cys119Gly	missense_variant	4/11	ENST00000263408.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
C9	ENST00000263408.5 linkuse as main transcript	c.355T>G	p.Cys119Gly	missense_variant	4/11	1	NM_001737.5	P2

Frequencies

GnomAD3 genomes

AF:

0.000138

AC:

AN:

152134

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000235

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000318

AC:

AN:

251298

Hom.:

AF XY:

0.000339

AC XY:

AN XY:

135834

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000405

Gnomad ASJ exome

AF:

0.00209

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000396

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000194

AC:

284

AN:

1461876

Hom.:

Cov.:

AF XY:

0.000193

AC XY:

140

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.000380

Gnomad4 ASJ exome

AF:

0.00172

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000178

Gnomad4 OTH exome

AF:

0.000265

GnomAD4 genome

AF:

0.000138

AC:

AN:

152134

Hom.:

Cov.:

AF XY:

0.000161

AC XY:

AN XY:

74318

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.000576

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000235

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.000346

Hom.:

Bravo

AF:

0.000174

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.000329

AC:

EpiCase

AF:

0.000327

EpiControl

AF:

0.000356

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Complement component 9 deficiency;C3810042:Age related macular degeneration 15

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jan 07, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	Mar 30, 2021	C9 NM_001737.4 exon 4 p.Cys119Gly (c.355T>G): This variant has been reported in the literature in 1 individual with complement C9 deficiency as a compound heterozygote, in trans with a loss-of-function variant (p.Ser427*). Both of these variants were implied to segregate with disease in 1 affected family member (Witzel-Schlomp 1998 PMID:9634479). This variant is present in 0.2% (22/10360) of Ashkenazi Jewish alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/5-39341369-A-C?dataset=gnomad_r2_1). This variant is present in ClinVar (Variation ID:17042). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In addition, in vitro functional studies predict that this variant will impact the protein (Witzel-Schlomp 1998 PMID:9634479). However, these studies may not accurately represent in vivo biological function. Of note, splice prediction tools suggest that this variant may affect splicing. However, further studies are needed to understand its impact. In summary, data on this variant is highly suspicious for disease, but requires further evidence for pathogenicity. Therefore, the clinical significance of this variant is uncertain. -

Complement component 9 deficiency

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 01, 1998

- -

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 22, 2024

This sequence change replaces cysteine, which is neutral and slightly polar, with glycine, which is neutral and non-polar, at codon 119 of the C9 protein (p.Cys119Gly). This variant is present in population databases (rs121909593, gnomAD 0.2%). This missense change has been observed in individual(s) with C9 deficiency (PMID: 9634479). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is also known as Cys98Gly. ClinVar contains an entry for this variant (Variation ID: 17042). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt C9 protein function with a positive predictive value of 80%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.92

BayesDel_addAF

Pathogenic

0.32

BayesDel_noAF

Pathogenic

0.54

CADD

Pathogenic

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.70

Eigen

Pathogenic

0.88

Eigen_PC

Pathogenic

0.72

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.85

M_CAP

Uncertain

0.18

MetaRNN

Pathogenic

0.96

MetaSVM

Pathogenic

0.91

MutationAssessor

Pathogenic

4.4

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.67

PROVEAN

Pathogenic

-11

REVEL

Pathogenic

0.94

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.99

MVP

0.95

MPC

0.27

ClinPred

0.99

GERP RS

5.1

Varity_R

0.99

gMVP

0.97

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over