1-56854962-C-A

Position:

• chr1-56854962-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000562.3(C8A):​c.61C>A​(p.Gln21Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,398 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: C8A NM_000562.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.70

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.23676708).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
C8A	NM_000562.3	c.61C>A	p.Gln21Lys	missense_variant	1/11	ENST00000361249.4	NP_000553.1
C8A	XM_017002234.2	c.61C>A	p.Gln21Lys	missense_variant	1/8		XP_016857723.1
C8A	XM_011542079.3	c.61C>A	p.Gln21Lys	missense_variant	1/8		XP_011540381.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
C8A	ENST00000361249.4	c.61C>A	p.Gln21Lys	missense_variant	1/11	1	NM_000562.3	ENSP00000354458.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461398 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 726996

Gnomad4 AFR exome AF: 0.0000299

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Type I complement component 8 deficiency Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jun 11, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.015	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0088	T
Eigen	Benign	-0.070
Eigen_PC	Benign	0.084
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.64	T
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.24	T
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	1.2	L
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.85	N
REVEL	Benign	0.28
Sift	Benign	0.059	T
Sift4G	Benign	0.62	T
Polyphen		0.44	B
Vest4		0.36
MutPred		0.40		Gain of ubiquitination at Q21 (P = 0.0267);
MVP		0.85
MPC		0.037
ClinPred		0.71	D
GERP RS		4.9
Varity_R		0.18
gMVP		0.39

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: rs1643959190; hg19: chr1-57320635;