Genetic Variant C8A:p.Arg485Pro (chr1-56912476-G-C) – 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_000562.3(C8A):c.1454G>C(p.Arg485Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000684 in 1,461,884 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R485H) has been classified as Benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000068 ( 0 hom. )

Consequence

C8A
NM_000562.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.252

Publications

19 publications found

Variant links:

Genes affected

C8A (HGNC:1352): (complement C8 alpha chain) C8 is a component of the complement system and contains three polypeptides, alpha, beta and gamma. This gene encodes the alpha subunit of C8. C8 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 complement C8 alpha-gamma deficiency. [provided by RefSeq, Nov 2008]

C8A Gene-Disease associations (from GenCC):

type I complement component 8 deficiency
Inheritance: AR Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

C8A 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, 0.812

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
C8A	NM_000562.3 link	c.1454G>C	p.Arg485Pro	missense_variant	Exon 10 of 11	ENST00000361249.4	NP_000553.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
C8A	ENST00000361249.4 link	c.1454G>C	p.Arg485Pro	missense_variant	Exon 10 of 11	1	NM_000562.3	ENSP00000354458.3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000796

AC:

AN:

251300

AF XY:

0.0000147

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000684

AC:

AN:

1461884

Hom.:

Cov.:

AF XY:

0.00000825

AC XY:

AN XY:

727244

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53414

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000899

AC:

AN:

1112008

Other (OTH)

AF:

0.00

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.64

BayesDel_addAF

Uncertain

0.058

BayesDel_noAF

Benign

-0.14

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.33

Eigen

Benign

-0.55

Eigen_PC

Benign

-0.77

FATHMM_MKL

Benign

0.14

LIST_S2

Benign

0.75

M_CAP

Uncertain

0.092

MetaRNN

Pathogenic

0.81

MetaSVM

Uncertain

0.61

MutationAssessor

Pathogenic

3.3

PhyloP100

0.25

PrimateAI

Benign

0.21

PROVEAN

Pathogenic

-5.4

REVEL

Uncertain

0.44

Sift

Uncertain

0.0070

Sift4G

Uncertain

0.014

Vest4

0.59

ClinPred

0.96

GERP RS

0.70

Varity_R

0.96

gMVP

0.92

Mutation Taster

=82/18

polymorphism

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over