1-56917684-C-T

Position:

• chr1-56917684-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000562.3(C8A):​c.1723C>T​(p.Pro575Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0118 in 1,614,162 control chromosomes in the GnomAD database, including 146 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict 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. P575L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0078 (5 hom., cov: 33)
  • Exomes 𝑓: 0.012 (141 hom.)
• Consequence: C8A NM_000562.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.674

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=0.013453692).
• BP6: Variant 1-56917684-C-T is Benign according to our data. Variant chr1-56917684-C-T is described in ClinVar as [Benign]. Clinvar id is 1166522.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00783 (1192/152294) while in subpopulation NFE AF= 0.0138 (940/68020). AF 95% confidence interval is 0.0131. There are 5 homozygotes in gnomad4. There are 496 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
C8A	NM_000562.3	c.1723C>T	p.Pro575Ser	missense_variant	11/11	ENST00000361249.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
C8A	ENST00000361249.4	c.1723C>T	p.Pro575Ser	missense_variant	11/11	1	NM_000562.3	P4

Frequencies

GnomAD3 genomes AF: 0.00784 AC: 1193 AN: 152178 Hom.: 5 Cov.: 33

Gnomad AFR AF: 0.00195

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00452

Gnomad ASJ AF: 0.0118

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.00348

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0138

Gnomad OTH AF: 0.00717

GnomAD3 exomes AF: 0.00892 AC: 2240 AN: 251064 Hom.: 18 AF XY: 0.00887 AC XY: 1203 AN XY: 135692

Gnomad AFR exome AF: 0.00234

Gnomad AMR exome AF: 0.00596

Gnomad ASJ exome AF: 0.00984

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00196

Gnomad FIN exome AF: 0.00402

Gnomad NFE exome AF: 0.0148

Gnomad OTH exome AF: 0.0113

GnomAD4 exome AF: 0.0123 AC: 17919 AN: 1461868 Hom.: 141 Cov.: 31 AF XY: 0.0117 AC XY: 8508 AN XY: 727238

Gnomad4 AFR exome AF: 0.00212

Gnomad4 AMR exome AF: 0.00593

Gnomad4 ASJ exome AF: 0.00991

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00191

Gnomad4 FIN exome AF: 0.00466

Gnomad4 NFE exome AF: 0.0145

Gnomad4 OTH exome AF: 0.0122

GnomAD4 genome AF: 0.00783 AC: 1192 AN: 152294 Hom.: 5 Cov.: 33 AF XY: 0.00666 AC XY: 496 AN XY: 74486

Gnomad4 AFR AF: 0.00195

Gnomad4 AMR AF: 0.00451

Gnomad4 ASJ AF: 0.0118

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00187

Gnomad4 FIN AF: 0.00348

Gnomad4 NFE AF: 0.0138

Gnomad4 OTH AF: 0.00710

Alfa AF: 0.0121 Hom.: 25

Bravo AF: 0.00764

TwinsUK AF: 0.0102 AC: 38

ALSPAC AF: 0.0130 AC: 50

ESP6500AA AF: 0.00204 AC: 9

ESP6500EA AF: 0.0109 AC: 94

ExAC AF: 0.0102 AC: 1234

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.0129

EpiControl AF: 0.0110

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2023	C8A: BP4, BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	13
DANN	Benign	0.15
DEOGEN2	Benign	0.015	T
Eigen	Benign	-0.81
Eigen_PC	Benign	-0.69
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.82	T
MetaRNN	Benign	0.013	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.90	L
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	0.020	N
REVEL	Benign	0.048
Sift	Benign	0.73	T
Sift4G	Benign	0.75	T
Polyphen		0.018	B
Vest4		0.12
MPC		0.037
ClinPred		0.0065	T
GERP RS		4.8
Varity_R		0.11
gMVP		0.38

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: rs41285938; hg19: chr1-57383357;