1-56912525-T-C

Variant names:

• chr1-56912525-T-C
• rs1754533
• NM_000562.3:c.1503T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000562.3(C8A):​c.1503T>C​(p.Pro501Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.062 in 1,614,104 control chromosomes in the GnomAD database, including 4,777 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.10 (1254 hom., cov: 33)
  • Exomes 𝑓: 0.058 (3523 hom.)
• Consequence: C8A NM_000562.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.701
• Publications: 6 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.57).
• BP6: Variant 1-56912525-T-C is Benign according to our data. Variant chr1-56912525-T-C is described in ClinVar as Benign. ClinVar VariationId is 402463.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.701 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.212 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C8A	NM_000562.3	MANE Select	c.1503T>C	p.Pro501Pro	synonymous	Exon 10 of 11	NP_000553.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C8A	ENST00000361249.4	TSL:1 MANE Select	c.1503T>C	p.Pro501Pro	synonymous	Exon 10 of 11	ENSP00000354458.3
	C8A	ENST00000695678.1		c.1503T>C	p.Pro501Pro	synonymous	Exon 10 of 11	ENSP00000512098.1
	C8A	ENST00000854265.1		c.1479T>C	p.Pro493Pro	synonymous	Exon 10 of 11	ENSP00000524324.1

Frequencies

GnomAD3 genomes AF: 0.102 AC: 15593 AN: 152164 Hom.: 1252 Cov.: 33

Gnomad AFR AF: 0.216

Gnomad AMI AF: 0.0482

Gnomad AMR AF: 0.108

Gnomad ASJ AF: 0.0415

Gnomad EAS AF: 0.0520

Gnomad SAS AF: 0.138

Gnomad FIN AF: 0.0470

Gnomad MID AF: 0.117

Gnomad NFE AF: 0.0457

Gnomad OTH AF: 0.104

GnomAD2 exomes AF: 0.0756 AC: 19000 AN: 251452 AF XY: 0.0752

Gnomad AFR exome AF: 0.224

Gnomad AMR exome AF: 0.0917

Gnomad ASJ exome AF: 0.0454

Gnomad EAS exome AF: 0.0518

Gnomad FIN exome AF: 0.0484

Gnomad NFE exome AF: 0.0455

Gnomad OTH exome AF: 0.0709

GnomAD4 exome AF: 0.0578 AC: 84518 AN: 1461820 Hom.: 3523 Cov.: 33 AF XY: 0.0596 AC XY: 43313 AN XY: 727218

African (AFR) AF: 0.228 AC: 7618 AN: 33474

American (AMR) AF: 0.0927 AC: 4147 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0430 AC: 1125 AN: 26136

East Asian (EAS) AF: 0.0650 AC: 2580 AN: 39698

South Asian (SAS) AF: 0.132 AC: 11410 AN: 86256

European-Finnish (FIN) AF: 0.0459 AC: 2451 AN: 53418

Middle Eastern (MID) AF: 0.112 AC: 648 AN: 5768

European-Non Finnish (NFE) AF: 0.0454 AC: 50446 AN: 1111950

Other (OTH) AF: 0.0678 AC: 4093 AN: 60396

GnomAD4 genome AF: 0.103 AC: 15615 AN: 152284 Hom.: 1254 Cov.: 33 AF XY: 0.102 AC XY: 7605 AN XY: 74474

African (AFR) AF: 0.216 AC: 8975 AN: 41554

American (AMR) AF: 0.108 AC: 1656 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0415 AC: 144 AN: 3468

East Asian (EAS) AF: 0.0520 AC: 269 AN: 5178

South Asian (SAS) AF: 0.139 AC: 669 AN: 4830

European-Finnish (FIN) AF: 0.0470 AC: 499 AN: 10614

Middle Eastern (MID) AF: 0.116 AC: 34 AN: 294

European-Non Finnish (NFE) AF: 0.0457 AC: 3109 AN: 68020

Other (OTH) AF: 0.102 AC: 216 AN: 2114

Alfa AF: 0.0681 Hom.: 301

Bravo AF: 0.110

Asia WGS AF: 0.107 AC: 374 AN: 3478

EpiCase AF: 0.0479

EpiControl AF: 0.0510

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
CADD	Benign	6.4
DANN	Benign	0.69
PhyloP100		-0.70
Mutation Taster		=94/6	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1754533; hg19: chr1-57378198; COSMIC: COSV63484450;