rs1013579

Variant names:

• chr1-56956811-C-A
• rs1013579
• NM_000066.4:c.349G>T

Your query was ambiguous. Multiple possible variants found:

• chr1-56956811-C-A
• chr1-56956811-C-G
• chr1-56956811-C-T

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_000066.4(C8B):​c.349G>T​(p.Gly117*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 31)
• Consequence: C8B NM_000066.4 stop_gained
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.950
• Publications: 32 publications found

Genes affected

C8B (HGNC:1353): (complement C8 beta chain) This gene encodes one of the three subunits of the complement component 8 (C8) protein. C8 is composed of equimolar amounts of alpha, beta and gamma subunits, which are encoded by three separate genes. C8 is one component of the membrane attack complex, which mediates cell lysis, and it initiates membrane penetration of the complex. This protein mediates the interaction of C8 with the C5b-7 membrane attack complex precursor. In humans deficiency of this protein is associated with increased risk of meningococcal infections. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jun 2013]

C8B Gene-Disease associations (from GenCC):

• type II complement component 8 deficiency

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000066.4. 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
	C8B	NM_000066.4	MANE Select	c.349G>T	p.Gly117*	stop_gained	Exon 3 of 12	NP_000057.3
	C8B	NM_001278543.2		c.193G>T	p.Gly65*	stop_gained	Exon 4 of 13	NP_001265472.2
	C8B	NM_001278544.2		c.163G>T	p.Gly55*	stop_gained	Exon 4 of 13	NP_001265473.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C8B	ENST00000371237.9	TSL:1 MANE Select	c.349G>T	p.Gly117*	stop_gained	Exon 3 of 12	ENSP00000360281.4
	C8B	ENST00000696164.1		c.349G>T	p.Gly117*	stop_gained	Exon 4 of 13	ENSP00000512454.1
	C8B	ENST00000695842.1		c.349G>T	p.Gly117*	stop_gained	Exon 3 of 11	ENSP00000512214.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 50

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	36
DANN	Uncertain	0.99
Eigen	Uncertain	0.28
Eigen_PC	Benign	0.085
FATHMM_MKL	Benign	0.56	D
PhyloP100		0.95
Vest4		0.70
GERP RS		-0.17
Mutation Taster		=4/196	disease causing (fs/PTC)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs1013579; hg19: chr1-57422484;