NM_000562.3:c.277C>A

Variant names:

• chr1-56875054-C-A
• rs652785
• NM_000562.3:c.277C>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.277C>A​(p.Gln93Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.376 in 1,612,406 control chromosomes in the GnomAD database, including 117,359 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.33 (8671 hom., cov: 32)
  • Exomes 𝑓: 0.38 (108688 hom.)
• Consequence: C8A NM_000562.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.0330
• Publications: 29 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=2.7430058E-4).
• BP6: Variant 1-56875054-C-A is Benign according to our data. Variant chr1-56875054-C-A is described in ClinVar as Benign. ClinVar VariationId is 17039.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.486 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.277C>A	p.Gln93Lys	missense	Exon 3 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.277C>A	p.Gln93Lys	missense	Exon 3 of 11	ENSP00000354458.3	P07357
	C8A	ENST00000695678.1		c.277C>A	p.Gln93Lys	missense	Exon 3 of 11	ENSP00000512098.1	A0A8Q3WL79
	C8A	ENST00000854265.1		c.253C>A	p.Gln85Lys	missense	Exon 3 of 11	ENSP00000524324.1

Frequencies

GnomAD3 genomes AF: 0.326 AC: 49463 AN: 151936 Hom.: 8678 Cov.: 32

Gnomad AFR AF: 0.210

Gnomad AMI AF: 0.319

Gnomad AMR AF: 0.249

Gnomad ASJ AF: 0.404

Gnomad EAS AF: 0.461

Gnomad SAS AF: 0.503

Gnomad FIN AF: 0.356

Gnomad MID AF: 0.392

Gnomad NFE AF: 0.381

Gnomad OTH AF: 0.338

GnomAD2 exomes AF: 0.365 AC: 91400 AN: 250228 AF XY: 0.379

Gnomad AFR exome AF: 0.206

Gnomad AMR exome AF: 0.211

Gnomad ASJ exome AF: 0.410

Gnomad EAS exome AF: 0.466

Gnomad FIN exome AF: 0.352

Gnomad NFE exome AF: 0.382

Gnomad OTH exome AF: 0.362

GnomAD4 exome AF: 0.381 AC: 556188 AN: 1460352 Hom.: 108688 Cov.: 39 AF XY: 0.386 AC XY: 280521 AN XY: 726472

African (AFR) AF: 0.205 AC: 6858 AN: 33452

American (AMR) AF: 0.214 AC: 9546 AN: 44650

Ashkenazi Jewish (ASJ) AF: 0.405 AC: 10566 AN: 26104

East Asian (EAS) AF: 0.419 AC: 16628 AN: 39660

South Asian (SAS) AF: 0.503 AC: 43337 AN: 86206

European-Finnish (FIN) AF: 0.351 AC: 18698 AN: 53346

Middle Eastern (MID) AF: 0.450 AC: 2585 AN: 5740

European-Non Finnish (NFE) AF: 0.383 AC: 425166 AN: 1110874

Other (OTH) AF: 0.378 AC: 22804 AN: 60320

GnomAD4 genome AF: 0.325 AC: 49461 AN: 152054 Hom.: 8671 Cov.: 32 AF XY: 0.326 AC XY: 24256 AN XY: 74306

African (AFR) AF: 0.210 AC: 8711 AN: 41496

American (AMR) AF: 0.249 AC: 3803 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.404 AC: 1401 AN: 3464

East Asian (EAS) AF: 0.460 AC: 2370 AN: 5154

South Asian (SAS) AF: 0.503 AC: 2414 AN: 4798

European-Finnish (FIN) AF: 0.356 AC: 3766 AN: 10566

Middle Eastern (MID) AF: 0.395 AC: 116 AN: 294

European-Non Finnish (NFE) AF: 0.381 AC: 25882 AN: 67986

Other (OTH) AF: 0.336 AC: 709 AN: 2108

Alfa AF: 0.369 Hom.: 47784

Bravo AF: 0.310

TwinsUK AF: 0.394 AC: 1460

ALSPAC AF: 0.384 AC: 1479

ESP6500AA AF: 0.212 AC: 935

ESP6500EA AF: 0.377 AC: 3239

ExAC AF: 0.368 AC: 44637

Asia WGS AF: 0.452 AC: 1575 AN: 3478

EpiCase AF: 0.394

EpiControl AF: 0.393

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	COMPLEMENT COMPONENT 8, ALPHA SUBUNIT, A/B POLYMORPHISM (1)
-	-	1	not specified (1)
-	-	1	Type I complement component 8 deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	7.5
DANN	Benign	0.65
DEOGEN2	Benign	0.011	T
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.60
FATHMM_MKL	Benign	0.045	N
LIST_S2	Benign	0.37	T
MetaRNN	Benign	0.00027	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-0.26	N
PhyloP100		0.033
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.91	N
REVEL	Benign	0.099
Sift	Benign	0.64	T
Sift4G	Benign	0.83	T
Polyphen		0.048	B
Vest4		0.051
MPC		0.037
ClinPred		0.0023	T
GERP RS		3.4
Varity_R		0.37
gMVP		0.47
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: rs652785; hg19: chr1-57340727; COSMIC: COSV63484431;