rs1342440

Positions:

• chr1-56917642-G-A
• chr1-56917642-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_000562.3(C8A):​c.1681G>A​(p.Glu561Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E561Q) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: C8A NM_000562.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.989

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.40505114).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
C8A	NM_000562.3	c.1681G>A	p.Glu561Lys	missense_variant	11/11	ENST00000361249.4	NP_000553.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
C8A	ENST00000361249.4	c.1681G>A	p.Glu561Lys	missense_variant	11/11	1	NM_000562.3	ENSP00000354458	P4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.028	T
Eigen	Benign	0.027
Eigen_PC	Benign	0.068
FATHMM_MKL	Benign	0.71	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.41	T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	0.55	N
MutationTaster	Benign	0.99	P
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.029
Sift	Benign	0.27	T
Sift4G	Benign	0.23	T
Polyphen		0.71	P
Vest4		0.26
MutPred		0.40		Gain of methylation at E561 (P = 0.0047);
MVP		0.71
MPC		0.088
ClinPred		0.53	D
GERP RS		2.7
Varity_R		0.18
gMVP		0.59

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: rs1342440; hg19: chr1-57383315; COSMIC: COSV104669199;