1-56867638-C-A

Variant names:

• chr1-56867638-C-A
• rs116201358
• NM_000562.3:c.107C>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000562.3(C8A):​c.107C>A​(p.Ala36Glu) variant causes a missense change. The variant allele was found at a frequency of 0.0137 in 1,613,714 control chromosomes in the GnomAD database, including 732 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A36V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0089 (52 hom., cov: 32)
  • Exomes 𝑓: 0.014 (680 hom.)
• Consequence: C8A NM_000562.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 4.35
• Publications: 8 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0024751425).
• BP6: Variant 1-56867638-C-A is Benign according to our data. Variant chr1-56867638-C-A is described in ClinVar as Benign. ClinVar VariationId is 1164179.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.11 is higher than 0.05.

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.107C>A	p.Ala36Glu	missense	Exon 2 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.107C>A	p.Ala36Glu	missense	Exon 2 of 11	ENSP00000354458.3	P07357
	C8A	ENST00000695678.1		c.107C>A	p.Ala36Glu	missense	Exon 2 of 11	ENSP00000512098.1	A0A8Q3WL79
	C8A	ENST00000854265.1		c.107C>A	p.Ala36Glu	missense	Exon 2 of 11	ENSP00000524324.1

Frequencies

GnomAD3 genomes AF: 0.00890 AC: 1354 AN: 152182 Hom.: 52 Cov.: 32

Gnomad AFR AF: 0.00152

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00288

Gnomad ASJ AF: 0.0147

Gnomad EAS AF: 0.00308

Gnomad SAS AF: 0.117

Gnomad FIN AF: 0.00245

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.00836

Gnomad OTH AF: 0.00574

GnomAD2 exomes AF: 0.0196 AC: 4928 AN: 251026 AF XY: 0.0252

Gnomad AFR exome AF: 0.000984

Gnomad AMR exome AF: 0.00368

Gnomad ASJ exome AF: 0.0167

Gnomad EAS exome AF: 0.00174

Gnomad FIN exome AF: 0.00374

Gnomad NFE exome AF: 0.00795

Gnomad OTH exome AF: 0.0176

GnomAD4 exome AF: 0.0142 AC: 20753 AN: 1461414 Hom.: 680 Cov.: 31 AF XY: 0.0174 AC XY: 12666 AN XY: 727028

African (AFR) AF: 0.00129 AC: 43 AN: 33462

American (AMR) AF: 0.00360 AC: 161 AN: 44670

Ashkenazi Jewish (ASJ) AF: 0.0162 AC: 422 AN: 26122

East Asian (EAS) AF: 0.000807 AC: 32 AN: 39672

South Asian (SAS) AF: 0.111 AC: 9596 AN: 86218

European-Finnish (FIN) AF: 0.00358 AC: 191 AN: 53400

Middle Eastern (MID) AF: 0.0189 AC: 109 AN: 5768

European-Non Finnish (NFE) AF: 0.00836 AC: 9291 AN: 1111728

Other (OTH) AF: 0.0150 AC: 908 AN: 60374

GnomAD4 genome AF: 0.00889 AC: 1354 AN: 152300 Hom.: 52 Cov.: 32 AF XY: 0.00999 AC XY: 744 AN XY: 74460

African (AFR) AF: 0.00152 AC: 63 AN: 41576

American (AMR) AF: 0.00288 AC: 44 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.0147 AC: 51 AN: 3470

East Asian (EAS) AF: 0.00309 AC: 16 AN: 5180

South Asian (SAS) AF: 0.118 AC: 568 AN: 4822

European-Finnish (FIN) AF: 0.00245 AC: 26 AN: 10614

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.00836 AC: 569 AN: 68038

Other (OTH) AF: 0.00520 AC: 11 AN: 2114

Alfa AF: 0.00905 Hom.: 56

Bravo AF: 0.00552

TwinsUK AF: 0.00917 AC: 34

ALSPAC AF: 0.0101 AC: 39

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.00860 AC: 74

ExAC AF: 0.0215 AC: 2608

Asia WGS AF: 0.0680 AC: 234 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Type I complement component 8 deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.059	T
Eigen	Benign	0.15
Eigen_PC	Benign	0.036
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.74	T
MetaRNN	Benign	0.0025	T
MetaSVM	Benign	-0.43	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		4.4
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.68	N
REVEL	Uncertain	0.39
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.0060	D
Polyphen		0.99	D
Vest4		0.22
MPC		0.19
ClinPred		0.033	T
GERP RS		5.1
Varity_R		0.24
gMVP		0.44
Mutation Taster		=98/2	polymorphism (auto)

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: rs116201358; hg19: chr1-57333311; COSMIC: COSV63485713;