1-56917642-G-A

Variant names:

• chr1-56917642-G-A
• rs1342440
• NM_000562.3:c.1681G>A

Variant summary

Our verdict is Uncertain significance. The variant received 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. 16/22 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 Benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: C8A NM_000562.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.989
• Publications: 19 publications found

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000562.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C8A	NM_000562.3	MANE Select	c.1681G>A	p.Glu561Lys	missense	Exon 11 of 11	NP_000553.1	P07357

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C8A	ENST00000361249.4	TSL:1 MANE Select	c.1681G>A	p.Glu561Lys	missense	Exon 11 of 11	ENSP00000354458.3	P07357
	C8A	ENST00000695678.1		c.1681G>A	p.Glu561Lys	missense	Exon 11 of 11	ENSP00000512098.1	A0A8Q3WL79
	C8A	ENST00000854265.1		c.1657G>A	p.Glu553Lys	missense	Exon 11 of 11	ENSP00000524324.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		0.99
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
Mutation Taster		=96/4	polymorphism

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

Other links and lift over

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