chr1-56867631-C-T

Position:

• chr1-56867631-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000562.3(C8A):​c.100C>T​(p.Pro34Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0044 in 1,613,714 control chromosomes in the GnomAD database, including 455 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0078 (54 hom., cov: 32)
  • Exomes 𝑓: 0.0041 (401 hom.)
• Consequence: C8A NM_000562.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.138

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0022082627).
• BP6: Variant 1-56867631-C-T is Benign according to our data. Variant chr1-56867631-C-T is described in ClinVar as [Benign]. Clinvar id is 1169492.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0634 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
C8A	NM_000562.3	c.100C>T	p.Pro34Ser	missense_variant	2/11	ENST00000361249.4
C8A	XM_017002234.2	c.100C>T	p.Pro34Ser	missense_variant	2/8
C8A	XM_011542079.3	c.100C>T	p.Pro34Ser	missense_variant	2/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
C8A	ENST00000361249.4	c.100C>T	p.Pro34Ser	missense_variant	2/11	1	NM_000562.3	P4

Frequencies

GnomAD3 genomes AF: 0.00774 AC: 1178 AN: 152162 Hom.: 53 Cov.: 32

Gnomad AFR AF: 0.00249

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0667

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000426

Gnomad OTH AF: 0.0105

GnomAD3 exomes AF: 0.0177 AC: 4440 AN: 251000 Hom.: 302 AF XY: 0.0130 AC XY: 1759 AN XY: 135636

Gnomad AFR exome AF: 0.00203

Gnomad AMR exome AF: 0.124

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.000185

Gnomad NFE exome AF: 0.000564

Gnomad OTH exome AF: 0.0113

GnomAD4 exome AF: 0.00405 AC: 5921 AN: 1461434 Hom.: 401 Cov.: 31 AF XY: 0.00336 AC XY: 2441 AN XY: 727042

Gnomad4 AFR exome AF: 0.00111

Gnomad4 AMR exome AF: 0.120

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.000393

Gnomad4 NFE exome AF: 0.000272

Gnomad4 OTH exome AF: 0.00349

GnomAD4 genome AF: 0.00776 AC: 1181 AN: 152280 Hom.: 54 Cov.: 32 AF XY: 0.00791 AC XY: 589 AN XY: 74462

Gnomad4 AFR AF: 0.00248

Gnomad4 AMR AF: 0.0668

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000283

Gnomad4 NFE AF: 0.000426

Gnomad4 OTH AF: 0.0104

Alfa AF: 0.00133 Hom.: 12

Bravo AF: 0.0139

ESP6500AA AF: 0.00227 AC: 10

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.0133 AC: 1617

Asia WGS AF: 0.00462 AC: 16 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000711

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

C8A-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 09, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	4.3
DANN	Benign	0.93
DEOGEN2	Benign	0.072	T
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.73
FATHMM_MKL	Benign	0.023	N
LIST_S2	Benign	0.50	T
MetaRNN	Benign	0.0022	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.4	M
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.26	T
PROVEAN	Pathogenic	-5.3	D
REVEL	Benign	0.25
Sift	Benign	0.069	T
Sift4G	Benign	0.064	T
Polyphen		0.59	P
Vest4		0.21
MPC		0.033
ClinPred		0.039	T
GERP RS		1.1
Varity_R		0.060
gMVP		0.51

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: rs143523574; hg19: chr1-57333304;