1-56867689-G-C

Position:

• chr1-56867689-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_000562.3(C8A):​c.158G>C​(p.Cys53Ser) 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 (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: C8A NM_000562.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.49

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.97

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
C8A	NM_000562.3	c.158G>C	p.Cys53Ser	missense_variant	2/11	ENST00000361249.4
C8A	XM_017002234.2	c.158G>C	p.Cys53Ser	missense_variant	2/8
C8A	XM_011542079.3	c.158G>C	p.Cys53Ser	missense_variant	2/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
C8A	ENST00000361249.4	c.158G>C	p.Cys53Ser	missense_variant	2/11	1	NM_000562.3	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 15, 2021

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. This variant has not been reported in the literature in individuals affected with C8A-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces cysteine, which is neutral and slightly polar, with serine, which is neutral and polar, at codon 53 of the C8A protein (p.Cys53Ser). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.010
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Benign	0.26	T
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.72	T
M_CAP	Benign	0.021	T
MetaRNN	Pathogenic	0.97	D
MetaSVM	Uncertain	-0.13	T
MutationAssessor	Pathogenic	3.3	M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.49	T
PROVEAN	Pathogenic	-8.7	D
REVEL	Uncertain	0.48
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.89
MutPred		0.86		Loss of catalytic residue at P52 (P = 0.0047);
MVP		0.76
MPC		0.18
ClinPred		1.0	D
GERP RS		5.1
Varity_R		0.93
gMVP		0.93

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-57333362;