rs12085435

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.782C>T(p.Pro261Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0519 in 1,613,678 control chromosomes in the GnomAD database, including 2,456 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 (★★).

Frequency

Genomes: 𝑓 0.053 ( 204 hom., cov: 32)

Exomes 𝑓: 0.052 ( 2252 hom. )

Consequence

C8B
NM_000066.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.734

Publications

16 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: Labcorp Genetics (formerly Invitae), Ambry Genetics

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=0.002777338).

BP6

Variant 1-56949637-G-A is Benign according to our data. Variant chr1-56949637-G-A is described in ClinVar as Benign. ClinVar VariationId is 1170461.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0645 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	UniProt
C8B	NM_000066.4	MANE Select	c.782C>T	p.Pro261Leu	missense	Exon 6 of 12	NP_000057.3	P07358
C8B	NM_001278543.2		c.626C>T	p.Pro209Leu	missense	Exon 7 of 13	NP_001265472.2
C8B	NM_001278544.2		c.596C>T	p.Pro199Leu	missense	Exon 7 of 13	NP_001265473.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
C8B	ENST00000371237.9	TSL:1 MANE Select	c.782C>T	p.Pro261Leu	missense	Exon 6 of 12	ENSP00000360281.4	P07358
C8B	ENST00000696164.1		c.782C>T	p.Pro261Leu	missense	Exon 7 of 13	ENSP00000512454.1	A0A8Q3WL56
C8B	ENST00000875298.1		c.782C>T	p.Pro261Leu	missense	Exon 7 of 13	ENSP00000545357.1

Frequencies

GnomAD3 genomes

AF:

0.0535

AC:

8127

AN:

151962

Hom.:

204

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0665

Gnomad AMI

AF:

0.0219

Gnomad AMR

AF:

0.0459

Gnomad ASJ

AF:

0.0591

Gnomad EAS

AF:

0.000771

Gnomad SAS

AF:

0.0632

Gnomad FIN

AF:

0.0329

Gnomad MID

AF:

0.0665

Gnomad NFE

AF:

0.0539

Gnomad OTH

AF:

0.0507

GnomAD2 exomes

AF:

0.0481

AC:

12072

AN:

251034

AF XY:

0.0492

show subpopulations

Gnomad AFR exome

AF:

0.0655

Gnomad AMR exome

AF:

0.0308

Gnomad ASJ exome

AF:

0.0548

Gnomad EAS exome

AF:

0.000218

Gnomad FIN exome

AF:

0.0329

Gnomad NFE exome

AF:

0.0568

Gnomad OTH exome

AF:

0.0509

GnomAD4 exome

AF:

0.0518

AC:

75673

AN:

1461598

Hom.:

2252

Cov.:

AF XY:

0.0522

AC XY:

37956

AN XY:

727122

show subpopulations

African (AFR)

AF:

0.0654

AC:

2191

AN:

33476

American (AMR)

AF:

0.0316

AC:

1414

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0573

AC:

1498

AN:

26130

East Asian (EAS)

AF:

0.000176

AC:

AN:

39676

South Asian (SAS)

AF:

0.0642

AC:

5534

AN:

86256

European-Finnish (FIN)

AF:

0.0342

AC:

1824

AN:

53384

Middle Eastern (MID)

AF:

0.0856

AC:

494

AN:

5768

European-Non Finnish (NFE)

AF:

0.0535

AC:

59528

AN:

1111798

Other (OTH)

AF:

0.0527

AC:

3183

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

3696

7392

11087

14783

18479

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2196

4392

6588

8784

10980

<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:

0.0535

AC:

8133

AN:

152080

Hom.:

204

Cov.:

AF XY:

0.0526

AC XY:

3913

AN XY:

74332

show subpopulations

African (AFR)

AF:

0.0665

AC:

2761

AN:

41500

American (AMR)

AF:

0.0458

AC:

700

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.0591

AC:

205

AN:

3470

East Asian (EAS)

AF:

0.000772

AC:

AN:

5178

South Asian (SAS)

AF:

0.0631

AC:

303

AN:

4804

European-Finnish (FIN)

AF:

0.0329

AC:

347

AN:

10536

Middle Eastern (MID)

AF:

0.0714

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0539

AC:

3666

AN:

67988

Other (OTH)

AF:

0.0501

AC:

106

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

390

780

1170

1560

1950

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

188

282

376

470

<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:

0.0544

Hom.:

695

Bravo

AF:

0.0533

TwinsUK

AF:

0.0542

AC:

201

ALSPAC

AF:

0.0509

AC:

196

ESP6500AA

AF:

0.0649

AC:

286

ESP6500EA

AF:

0.0556

AC:

478

ExAC

AF:

0.0497

AC:

6039

Asia WGS

AF:

0.0290

AC:

100

AN:

3478

EpiCase

AF:

0.0573

EpiControl

AF:

0.0600

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.65

CADD

Benign

4.4

(source)

DANN

Benign

0.41

DEOGEN2

Benign

0.073

Eigen

Benign

-0.98

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.10

LIST_S2

Benign

0.23

MetaRNN

Benign

0.0028

MetaSVM

Benign

-1.0

PhyloP100

0.73

PrimateAI

Benign

0.29

PROVEAN

Uncertain

-3.5

REVEL

Benign

0.041

Sift

Benign

0.19

Sift4G

Benign

0.14

Polyphen

0.012

Vest4

0.033

MPC

0.041

ClinPred

0.021

GERP RS

0.85

gMVP

0.65

Mutation Taster

=91/9

polymorphism (auto)

(source)

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

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

Computational scores

Splicing

Publications

Other links and lift over