1-56956799-G-C

Variant names:

• chr1-56956799-G-C
• rs150022116
• NM_000066.4:c.361C>G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_000066.4(C8B):​c.361C>G​(p.Arg121Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000031 in 1,613,792 control chromosomes in the GnomAD database, with no homozygous occurrence. 11/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. R121R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: C8B NM_000066.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.36

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
C8B	NM_000066.4	c.361C>G	p.Arg121Gly	missense_variant	Exon 3 of 12	ENST00000371237.9	NP_000057.3
C8B	NM_001278543.2	c.205C>G	p.Arg69Gly	missense_variant	Exon 4 of 13		NP_001265472.2
C8B	NM_001278544.2	c.175C>G	p.Arg59Gly	missense_variant	Exon 4 of 13		NP_001265473.2
C8B	XM_047429957.1	c.361C>G	p.Arg121Gly	missense_variant	Exon 3 of 7		XP_047285913.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
C8B	ENST00000371237.9	c.361C>G	p.Arg121Gly	missense_variant	Exon 3 of 12	1	NM_000066.4	ENSP00000360281.4

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152002 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461790 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727210

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152002 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74226

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.028	.;T;.
Eigen	Benign	-0.12
Eigen_PC	Benign	-0.011
FATHMM_MKL	Benign	0.33	N
LIST_S2	Uncertain	0.88	.;D;D
M_CAP	Benign	0.0072	T
MetaRNN	Uncertain	0.51	D;D;D
MetaSVM	Benign	-1.1	T
PrimateAI	Benign	0.40	T
PROVEAN	Uncertain	-2.6	D;N;N
REVEL	Benign	0.18
Sift	Benign	0.15	T;T;T
Sift4G	Benign	0.40	T;T;T
Polyphen		0.98, 0.65	.;D;P
Vest4		0.54
MutPred		0.67		Loss of MoRF binding (P = 0.082);.;.;
MVP		0.55
MPC		0.13
ClinPred		0.83	D
GERP RS		5.4
gMVP		0.63

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs150022116; hg19: chr1-57422472;