1-56956811-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000066.4(C8B):c.349G>A(p.Gly117Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.973 in 1,614,046 control chromosomes in the GnomAD database, including 764,602 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G117E) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.98 ( 72967 hom., cov: 31)

Exomes 𝑓: 0.97 ( 691635 hom. )

Consequence

C8B
NM_000066.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.950

Publications

32 publications found

Variant links:

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 deficiency
Inheritance: AR Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

C8B links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=5.8007174E-7).

BP6

Variant 1-56956811-C-T is Benign according to our data. Variant chr1-56956811-C-T is described in ClinVar as Benign. ClinVar VariationId is 1169777.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.986 is higher than 0.05.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
C8B	NM_000066.4	MANE Select	c.349G>A	p.Gly117Arg	missense	Exon 3 of 12	NP_000057.3
C8B	NM_001278543.2		c.193G>A	p.Gly65Arg	missense	Exon 4 of 13	NP_001265472.2
C8B	NM_001278544.2		c.163G>A	p.Gly55Arg	missense	Exon 4 of 13	NP_001265473.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
C8B	ENST00000371237.9	TSL:1 MANE Select	c.349G>A	p.Gly117Arg	missense	Exon 3 of 12	ENSP00000360281.4
C8B	ENST00000696164.1		c.349G>A	p.Gly117Arg	missense	Exon 4 of 13	ENSP00000512454.1
C8B	ENST00000875298.1		c.349G>A	p.Gly117Arg	missense	Exon 4 of 13	ENSP00000545357.1

Frequencies

GnomAD3 genomes

AF:

0.979

AC:

148906

AN:

152126

Hom.:

72908

Cov.:

show subpopulations

Gnomad AFR

AF:

0.994

Gnomad AMI

AF:

0.997

Gnomad AMR

AF:

0.973

Gnomad ASJ

AF:

0.970

Gnomad EAS

AF:

0.999

Gnomad SAS

AF:

0.989

Gnomad FIN

AF:

0.985

Gnomad MID

AF:

0.959

Gnomad NFE

AF:

0.968

Gnomad OTH

AF:

0.973

GnomAD2 exomes

AF:

0.977

AC:

245666

AN:

251372

AF XY:

0.977

show subpopulations

Gnomad AFR exome

AF:

0.994

Gnomad AMR exome

AF:

0.975

Gnomad ASJ exome

AF:

0.974

Gnomad EAS exome

AF:

1.00

Gnomad FIN exome

AF:

0.982

Gnomad NFE exome

AF:

0.968

Gnomad OTH exome

AF:

0.967

GnomAD4 exome

AF:

0.973

AC:

1421897

AN:

1461802

Hom.:

691635

Cov.:

AF XY:

0.973

AC XY:

707467

AN XY:

727216

show subpopulations

African (AFR)

AF:

0.995

AC:

33307

AN:

33476

American (AMR)

AF:

0.974

AC:

43579

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.972

AC:

25411

AN:

26136

East Asian (EAS)

AF:

1.00

AC:

39698

AN:

39700

South Asian (SAS)

AF:

0.988

AC:

85250

AN:

86258

European-Finnish (FIN)

AF:

0.980

AC:

52376

AN:

53418

Middle Eastern (MID)

AF:

0.969

AC:

5587

AN:

5768

European-Non Finnish (NFE)

AF:

0.969

AC:

1077885

AN:

1111928

Other (OTH)

AF:

0.974

AC:

58804

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

Heterozygous variant carriers

2178

4356

6533

8711

10889

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

21650

43300

64950

86600

108250

<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:

0.979

AC:

149024

AN:

152244

Hom.:

72967

Cov.:

AF XY:

0.980

AC XY:

72926

AN XY:

74418

show subpopulations

African (AFR)

AF:

0.994

AC:

41318

AN:

41548

American (AMR)

AF:

0.973

AC:

14868

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.970

AC:

3369

AN:

3472

East Asian (EAS)

AF:

0.999

AC:

5137

AN:

5140

South Asian (SAS)

AF:

0.989

AC:

4769

AN:

4822

European-Finnish (FIN)

AF:

0.985

AC:

10456

AN:

10618

Middle Eastern (MID)

AF:

0.959

AC:

282

AN:

294

European-Non Finnish (NFE)

AF:

0.968

AC:

65861

AN:

68042

Other (OTH)

AF:

0.973

AC:

2055

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

153

305

458

610

763

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

914

1828

2742

3656

4570

<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:

0.970

Hom.:

240993

Bravo

AF:

0.978

TwinsUK

AF:

0.970

AC:

3596

ALSPAC

AF:

0.977

AC:

3765

ESP6500AA

AF:

0.993

AC:

4373

ESP6500EA

AF:

0.967

AC:

8318

ExAC

AF:

0.977

AC:

118661

Asia WGS

AF:

0.995

AC:

3462

AN:

3478

EpiCase

AF:

0.965

EpiControl

AF:

0.966

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Type II complement component 8 deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.042

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.61

CADD

Benign

9.8

(source)

DANN

Benign

0.53

DEOGEN2

Benign

0.0014

Eigen

Benign

-0.71

Eigen_PC

Benign

-0.59

FATHMM_MKL

Benign

0.10

LIST_S2

Benign

0.048

MetaRNN

Benign

5.8e-7

MetaSVM

Benign

-0.95

PhyloP100

0.95

PrimateAI

Uncertain

0.49

PROVEAN

Benign

2.9

REVEL

Benign

0.036

Sift

Benign

1.0

Sift4G

Benign

0.76

Polyphen

0.0

Vest4

0.081

MutPred

0.32

Gain of disorder (P = 0.0794)

MPC

0.041

ClinPred

0.0050

GERP RS

-0.17

gMVP

0.38

Mutation Taster

=98/2

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.090

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

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over