rs398122868
Variant summary
Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1PM2PP5
The NM_000066.4(C8B):c.1041_1047dupGGCTGTG(p.Leu350GlyfsTer8) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000752 in 1,461,838 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (no stars). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000075 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
C8B
NM_000066.4 frameshift
NM_000066.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: -0.197
Publications
2 publications found
Genes affected
C8B (HGNC:1353): (complement C8 beta chain) This gene encodes one of the three subunits of the complement component 8 (C8) protein. C8 is composed of equimolar amounts of alpha, beta and gamma subunits, which are encoded by three separate genes. C8 is one component of the membrane attack complex, which mediates cell lysis, and it initiates membrane penetration of the complex. This protein mediates the interaction of C8 with the C5b-7 membrane attack complex precursor. In humans deficiency of this protein is associated with increased risk of meningococcal infections. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jun 2013]
C8B Gene-Disease associations (from GenCC):
- type II complement component 8 deficiencyInheritance: AR Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
Genome browser will be placed here
ACMG classification
Classification was made for transcript
Our verdict: Pathogenic. The variant received 11 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 1-56945878-G-GCACAGCC is Pathogenic according to our data. Variant chr1-56945878-G-GCACAGCC is described in ClinVar as Pathogenic. ClinVar VariationId is 35597.Status of the report is no_assertion_criteria_provided, 0 stars.
Variant Effect in Transcripts
ACMG analysis was done for transcript: NM_000066.4. 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 |
|---|---|---|---|---|---|---|---|---|---|
| C8B | NM_000066.4 | MANE Select | c.1041_1047dupGGCTGTG | p.Leu350GlyfsTer8 | frameshift | Exon 7 of 12 | NP_000057.3 | ||
| C8B | NM_001278543.2 | c.885_891dupGGCTGTG | p.Leu298GlyfsTer8 | frameshift | Exon 8 of 13 | NP_001265472.2 | |||
| C8B | NM_001278544.2 | c.855_861dupGGCTGTG | p.Leu288GlyfsTer8 | frameshift | Exon 8 of 13 | NP_001265473.2 |
Ensembl Transcripts
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| C8B | ENST00000371237.9 | TSL:1 MANE Select | c.1041_1047dupGGCTGTG | p.Leu350GlyfsTer8 | frameshift | Exon 7 of 12 | ENSP00000360281.4 | ||
| C8B | ENST00000696164.1 | c.1041_1047dupGGCTGTG | p.Leu350GlyfsTer8 | frameshift | Exon 8 of 13 | ENSP00000512454.1 | |||
| C8B | ENST00000695842.1 | c.1041_1047dupGGCTGTG | p.Leu350GlyfsTer8 | frameshift | Exon 7 of 11 | ENSP00000512214.1 |
Frequencies
GnomAD3 genomes 0.00000657 AC: 1AN: 152136Hom.: 0 Cov.: 32 show subpopulations
GnomAD3 genomes
AF:
AC:
1
AN:
152136
Hom.:
Cov.:
32
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
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Gnomad ASJ
AF:
Gnomad EAS
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Gnomad SAS
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Gnomad FIN
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Gnomad MID
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Gnomad NFE
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Gnomad OTH
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GnomAD4 exome AF: 0.00000752 AC: 11AN: 1461838Hom.: 0 Cov.: 32 AF XY: 0.00000825 AC XY: 6AN XY: 727226 show subpopulations
GnomAD4 exome
AF:
AC:
11
AN:
1461838
Hom.:
Cov.:
32
AF XY:
AC XY:
6
AN XY:
727226
show subpopulations
African (AFR)
AF:
AC:
0
AN:
33480
American (AMR)
AF:
AC:
0
AN:
44720
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
26134
East Asian (EAS)
AF:
AC:
0
AN:
39696
South Asian (SAS)
AF:
AC:
0
AN:
86258
European-Finnish (FIN)
AF:
AC:
0
AN:
53414
Middle Eastern (MID)
AF:
AC:
0
AN:
5766
European-Non Finnish (NFE)
AF:
AC:
11
AN:
1111974
Other (OTH)
AF:
AC:
0
AN:
60396
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.507
Heterozygous variant carriers
0
1
2
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6
0.00
0.20
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0.95
Allele balance
Age Distribution
Exome Het
Variant carriers
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Age
GnomAD4 genome 0.00000657 AC: 1AN: 152136Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74304 show subpopulations
GnomAD4 genome
Data not reliable, filtered out with message: AS_VQSR
AF:
AC:
1
AN:
152136
Hom.:
Cov.:
32
AF XY:
AC XY:
1
AN XY:
74304
show subpopulations
African (AFR)
AF:
AC:
0
AN:
41436
American (AMR)
AF:
AC:
0
AN:
15272
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
3472
East Asian (EAS)
AF:
AC:
0
AN:
5170
South Asian (SAS)
AF:
AC:
0
AN:
4822
European-Finnish (FIN)
AF:
AC:
0
AN:
10614
Middle Eastern (MID)
AF:
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
AC:
1
AN:
68032
Other (OTH)
AF:
AC:
0
AN:
2090
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.575
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Age Distribution
Genome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
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>80
Age
Alfa
AF:
Hom.:
Bravo
AF:
ClinVar
ClinVar submissions as Germline
Significance:Pathogenic
Revision:no assertion criteria provided
Pathogenic
VUS
Benign
Condition
1
-
-
Type II complement component 8 deficiency (1)
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
PhyloP100
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
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