NM_000562.3:c.1723C>T

Variant names:

• chr1-56917684-C-T
• rs41285938
• NM_000562.3:c.1723C>T

Variant summary

Our verdict is Benign. The variant received -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. 16/21 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 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:3
• Conservation: PhyloP100: 0.674
• 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=0.013453692).
• BP6: Variant 1-56917684-C-T is Benign according to our data. Variant chr1-56917684-C-T is described in ClinVar as Benign. ClinVar VariationId 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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 AR gene

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.1723C>T	p.Pro575Ser	missense	Exon 11 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.1723C>T	p.Pro575Ser	missense	Exon 11 of 11	ENSP00000354458.3
	C8A	ENST00000695678.1		c.1723C>T	p.Pro575Ser	missense	Exon 11 of 11	ENSP00000512098.1
	C8A	ENST00000695677.1		c.1672C>T	p.Pro558Ser	missense	Exon 11 of 11	ENSP00000512097.1

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

GnomAD2 exomes AF: 0.00892 AC: 2240 AN: 251064 AF XY: 0.00887

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 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

African (AFR) AF: 0.00212 AC: 71 AN: 33480

American (AMR) AF: 0.00593 AC: 265 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00991 AC: 259 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00191 AC: 165 AN: 86256

European-Finnish (FIN) AF: 0.00466 AC: 249 AN: 53418

Middle Eastern (MID) AF: 0.00122 AC: 7 AN: 5754

European-Non Finnish (NFE) AF: 0.0145 AC: 16164 AN: 1112004

Other (OTH) AF: 0.0122 AC: 738 AN: 60396

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

African (AFR) AF: 0.00195 AC: 81 AN: 41572

American (AMR) AF: 0.00451 AC: 69 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0118 AC: 41 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00187 AC: 9 AN: 4822

European-Finnish (FIN) AF: 0.00348 AC: 37 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.0138 AC: 940 AN: 68020

Other (OTH) AF: 0.00710 AC: 15 AN: 2114

Alfa AF: 0.0114 Hom.: 35

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:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Sep 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

C8A: BP4, BS1, BS2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		0.67
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
Mutation Taster		=95/5	polymorphism

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: rs41285938; hg19: chr1-57383357;