1-56912476-G-C

Position:

• chr1-56912476-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

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. R485L) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: C8A NM_000562.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.252

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 Uncertain_significance. Variant got 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/exons	MANE	UniProt
C8A	NM_000562.3	c.1454G>C	p.Arg485Pro	missense_variant	10/11	ENST00000361249.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
C8A	ENST00000361249.4	c.1454G>C	p.Arg485Pro	missense_variant	10/11	1	NM_000562.3	P4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000796 AC: 2 AN: 251300 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135868

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 SAS 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: 10 AN: 1461884 Hom.: 0 Cov.: 33 AF XY: 0.00000825 AC XY: 6 AN XY: 727244

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000899

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

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	T
BayesDel_noAF	Benign	-0.14
CADD	Benign	15
DANN	Benign	0.97
DEOGEN2	Benign	0.33	T
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.77
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.75	T
M_CAP	Uncertain	0.092	D
MetaRNN	Pathogenic	0.81	D
MetaSVM	Uncertain	0.61	D
MutationAssessor	Pathogenic	3.3	M
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.21	T
PROVEAN	Pathogenic	-5.4	D
REVEL	Uncertain	0.44
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.014	D
Polyphen		0.96	D
Vest4		0.59
MutPred		0.60		Gain of glycosylation at R485 (P = 0.0424);
MVP		0.84
MPC		0.23
ClinPred		0.96	D
GERP RS		0.70
Varity_R		0.96
gMVP		0.92

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

LitVar

Other links and lift over

dbSNP: rs1620075; hg19: chr1-57378149;