NM_001737.5:c.162C>A

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 16P and 1B. PVS1PP5_Very_StrongBS2_Supporting

The NM_001737.5(C9):c.162C>A(p.Cys54*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00119 in 1,591,052 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. C54C) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.00093 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0012 ( 2 hom. )

Consequence

C9
NM_001737.5 stop_gained

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9

Conservation

PhyloP100: 0.969

Publications

4 publications found

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 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

C9 links:

ENSG00000289699 (HGNC:):

ENSG00000289699 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 15 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PP5

Variant 5-39342112-G-T is Pathogenic according to our data. Variant chr5-39342112-G-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 17041.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAdExome4 at 2 Unknown,AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

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.162C>A	p.Cys54*	stop_gained	Exon 2 of 11	NP_001728.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
C9	ENST00000263408.5	TSL:1 MANE Select	c.162C>A	p.Cys54*	stop_gained	Exon 2 of 11	ENSP00000263408.4
C9	ENST00000509186.6	TSL:3	c.90C>A	p.Cys30*	stop_gained	Exon 2 of 11	ENSP00000512235.1
C9	ENST00000695880.1		c.162C>A	p.Cys54*	stop_gained	Exon 2 of 10	ENSP00000512236.1

Frequencies

GnomAD3 genomes

AF:

0.000927

AC:

141

AN:

152144

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000314

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000720

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00207

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00135

Gnomad OTH

AF:

0.000955

GnomAD2 exomes

AF:

0.000891

AC:

224

AN:

251468

AF XY:

0.000846

show subpopulations

Gnomad AFR exome

AF:

0.000369

Gnomad AMR exome

AF:

0.000231

Gnomad ASJ exome

AF:

0.000496

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00152

Gnomad NFE exome

AF:

0.00147

Gnomad OTH exome

AF:

0.000814

GnomAD4 exome

AF:

0.00122

AC:

1752

AN:

1438790

Hom.:

Cov.:

AF XY:

0.00125

AC XY:

895

AN XY:

717426

show subpopulations

African (AFR)

AF:

0.000212

AC:

AN:

33004

American (AMR)

AF:

0.000246

AC:

AN:

44698

Ashkenazi Jewish (ASJ)

AF:

0.000846

AC:

AN:

25994

East Asian (EAS)

AF:

0.00

AC:

AN:

39604

South Asian (SAS)

AF:

0.0000233

AC:

AN:

85862

European-Finnish (FIN)

AF:

0.00131

AC:

AN:

53404

Middle Eastern (MID)

AF:

0.000174

AC:

AN:

5736

European-Non Finnish (NFE)

AF:

0.00145

AC:

1587

AN:

1090874

Other (OTH)

AF:

0.000872

AC:

AN:

59614

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

Heterozygous variant carriers

153

229

306

382

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

104

156

208

260

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000926

AC:

141

AN:

152262

Hom.:

Cov.:

AF XY:

0.00101

AC XY:

AN XY:

74460

show subpopulations

African (AFR)

AF:

0.000313

AC:

AN:

41538

American (AMR)

AF:

0.000719

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00207

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00135

AC:

AN:

68016

Other (OTH)

AF:

0.000945

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000640

Hom.:

Bravo

AF:

0.000933

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.00130

AC:

ESP6500AA

AF:

0.00113

AC:

ESP6500EA

AF:

0.00244

AC:

ExAC

AF:

0.000988

AC:

120

EpiCase

AF:

0.00142

EpiControl

AF:

0.00124

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Complement component 9 deficiency

Pathogenic:4

Apr 14, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

Jul 01, 1998

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

Jul 28, 2023

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.Cys54X variant in C9 has been reported in at least 2 compound heterozygous individuals with C9 deficiency and segregated with disease at least 1 affected family member (selected publications: Hobart 1997 PMID: 9182899, Witzel-Schlomp 1997 PMID: 9144525, Witzel-Schlömp 1998 PMID: 9634479). It has been identified in 0.2% (22/10620) of Finnish chromosomes by gnomAD v3.1.2 (https://gnomad.broadinstitute.org/) and has also been reported in ClinVar (Variation ID 17041). This nonsense variant leads to a premature termination codon at position 54, which is predicted to lead to a truncated or absent protein. Loss of function of the C9 gene is an established disease mechanism in autosomal recessive C9 deficiency. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive C9 deficiency. ACMG/AMP criteria applied: PVS1, PM3, PP1

Feb 28, 2017

ITMI

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

not provided

Pathogenic:3

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change creates a premature translational stop signal (p.Cys54*) in the C9 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in C9 are known to be pathogenic (PMID: 9144525, 9570574). This variant is present in population databases (rs34000044, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This premature translational stop signal has been observed in individual(s) with C9-deficiency (PMID: 9144525, 9634479). ClinVar contains an entry for this variant (Variation ID: 17041). For these reasons, this variant has been classified as Pathogenic.

Apr 14, 2015

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The C54X variant in the C9 gene has been reported previously in association with complement 9 deficiency (Witzel-Schlomp et al., 1997). This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The NHLBI ESP Exome Sequencing Project reports C54X was observed at a frequency of 0.24%, 21/8600 alleles from individuals of European ancestry, and at a frequency of 0.11%, 5/4406 alleles from individuals of African American ancestry indicating it may be a rare variant in this population. We interpret C54X as a pathogenic variant.

May 27, 2022

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Pathogenic:1

Apr 07, 2022

Fulgent Genetics, Fulgent Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

C9-related disorder

Pathogenic:1

Sep 06, 2024

PreventionGenetics, part of Exact Sciences

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

The C9 c.162C>A variant is predicted to result in premature protein termination (p.Cys54*). This variant has been reported to be causative for complement 9 deficiency (reported as AA33, Witzel-Schlömp et al. 1997. PubMed ID: 9144525). This variant is reported in 0.14% of alleles in individuals of European (Finnish) descent in gnomAD. Nonsense variants in C9 are expected to be pathogenic. This variant is interpreted as pathogenic.

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.24

BayesDel_noAF

Pathogenic

0.54

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

Eigen

Uncertain

0.28

Eigen_PC

Benign

0.095

FATHMM_MKL

Benign

0.59

PhyloP100

0.97

Vest4

0.65

GERP RS

2.9

Mutation Taster

=5/195

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over