Genetic Variant C8B:p.Pro573Ser (chr1-56929463-G-A) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_000066.4(C8B):c.1717C>T(p.Pro573Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. P573P) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Consequence

C8B
NM_000066.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.87

Publications

0 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.822

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.1717C>T	p.Pro573Ser	missense	Exon 12 of 12	NP_000057.3	P07358
C8B	NM_001278543.2		c.1561C>T	p.Pro521Ser	missense	Exon 13 of 13	NP_001265472.2
C8B	NM_001278544.2		c.1531C>T	p.Pro511Ser	missense	Exon 13 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.1717C>T	p.Pro573Ser	missense	Exon 12 of 12	ENSP00000360281.4	P07358
C8B	ENST00000696164.1		c.1717C>T	p.Pro573Ser	missense	Exon 13 of 13	ENSP00000512454.1	A0A8Q3WL56
C8B	ENST00000875298.1		c.1717C>T	p.Pro573Ser	missense	Exon 13 of 13	ENSP00000545357.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.22

BayesDel_addAF

Uncertain

0.052

BayesDel_noAF

Benign

-0.16

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.44

Eigen

Pathogenic

0.76

Eigen_PC

Uncertain

0.65

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.96

M_CAP

Benign

0.015

MetaRNN

Pathogenic

0.82

MetaSVM

Benign

-0.61

PhyloP100

5.9

PrimateAI

Benign

0.35

PROVEAN

Pathogenic

-6.9

REVEL

Uncertain

0.39

Sift

Uncertain

0.0070

Sift4G

Uncertain

0.013

Polyphen

1.0

Vest4

0.70

MutPred

0.61

Loss of catalytic residue at P573 (P = 0.0264)

MVP

0.71

MPC

0.27

ClinPred

0.99

GERP RS

3.8

gMVP

0.77

Mutation Taster

=30/70

disease causing

(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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over