rs398122867

Positions:

• chr1-56952108-CG-C

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_000066.4(C8B):​c.605del​(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). 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

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]

ACMG classification

Verdict is Pathogenic. Variant got 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 id is 35596.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
C8B	NM_000066.4	c.605del	p.Pro202ArgfsTer5	frameshift_variant	5/12	ENST00000371237.9	NP_000057.3
C8B	NM_001278543.2	c.449del	p.Pro150ArgfsTer5	frameshift_variant	6/13		NP_001265472.2
C8B	NM_001278544.2	c.419del	p.Pro140ArgfsTer5	frameshift_variant	6/13		NP_001265473.2
C8B	XM_047429957.1	c.605del	p.Pro202ArgfsTer5	frameshift_variant	5/7		XP_047285913.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
C8B	ENST00000371237.9	c.605del	p.Pro202ArgfsTer5	frameshift_variant	5/12	1	NM_000066.4	ENSP00000360281	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Type II complement component 8 deficiency Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 15, 1995

- -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs398122867; hg19: chr1-57417781;