NM_000066.4:c.1681C>A

Variant names:

• chr1-56929499-G-T
• NM_000066.4:c.1681C>A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_000066.4(C8B):​c.1681C>A​(p.Arg561Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000616 in 1,461,464 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R561C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: C8B NM_000066.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.61

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06267828).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
C8B	NM_000066.4	c.1681C>A	p.Arg561Ser	missense_variant	Exon 12 of 12	ENST00000371237.9	NP_000057.3
C8B	NM_001278543.2	c.1525C>A	p.Arg509Ser	missense_variant	Exon 13 of 13		NP_001265472.2
C8B	NM_001278544.2	c.1495C>A	p.Arg499Ser	missense_variant	Exon 13 of 13		NP_001265473.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
C8B	ENST00000371237.9	c.1681C>A	p.Arg561Ser	missense_variant	Exon 12 of 12	1	NM_000066.4	ENSP00000360281.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1461464 Hom.: 0 Cov.: 33 AF XY: 0.00000550 AC XY: 4 AN XY: 727044

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: 0.00000809

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	17
DANN	Benign	0.91
DEOGEN2	Benign	0.0056	.;T;.
Eigen	Benign	-0.57
Eigen_PC	Benign	-0.47
FATHMM_MKL	Benign	0.58	D
LIST_S2	Uncertain	0.91	.;D;D
M_CAP	Benign	0.0042	T
MetaRNN	Benign	0.063	T;T;T
MetaSVM	Benign	-1.0	T
PrimateAI	Benign	0.18	T
PROVEAN	Benign	0.070	N;N;N
REVEL	Benign	0.053
Sift	Benign	0.66	T;T;T
Sift4G	Benign	0.41	T;T;T
Polyphen		0.039, 0.020	.;B;B
Vest4		0.15
MutPred		0.38		Gain of phosphorylation at R561 (P = 0.0275);.;.;
MVP		0.33
MPC		0.042
ClinPred		0.13	T
GERP RS		2.7
gMVP		0.43

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-57395172;