rs398122867

Variant names:

• chr1-56952108-CG-C
• rs398122867
• NM_000066.4:c.605delC

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_000066.4(C8B):​c.605delC​(p.Pro202ArgfsTer5) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. P202P) has been classified as Benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: C8B NM_000066.4 frameshift
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.58
• Publications: 2 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 11 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
• PP5: Variant 1-56952108-CG-C is Pathogenic according to our data. Variant chr1-56952108-CG-C is described in ClinVar as Pathogenic. ClinVar VariationId is 35596.Status of the report is no_assertion_criteria_provided, 0 stars.

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.605delC	p.Pro202ArgfsTer5	frameshift	Exon 5 of 12	NP_000057.3
	C8B	NM_001278543.2		c.449delC	p.Pro150ArgfsTer5	frameshift	Exon 6 of 13	NP_001265472.2
	C8B	NM_001278544.2		c.419delC	p.Pro140ArgfsTer5	frameshift	Exon 6 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.605delC	p.Pro202ArgfsTer5	frameshift	Exon 5 of 12	ENSP00000360281.4
	C8B	ENST00000696164.1		c.605delC	p.Pro202ArgfsTer5	frameshift	Exon 6 of 13	ENSP00000512454.1
	C8B	ENST00000695842.1		c.605delC	p.Pro202ArgfsTer5	frameshift	Exon 5 of 11	ENSP00000512214.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Type II complement component 8 deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.6
Mutation Taster		=0/200	disease causing (ClinVar)

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: rs398122867; hg19: chr1-57417781;