1-56929463-G-T

Variant names:

• chr1-56929463-G-T
• NM_000066.4:c.1717C>A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_000066.4(C8B):​c.1717C>A​(p.Pro573Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000342 in 1,460,786 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. P573S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: C8B NM_000066.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.87

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.845

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
C8B	NM_000066.4	c.1717C>A	p.Pro573Thr	missense_variant	Exon 12 of 12	ENST00000371237.9	NP_000057.3
C8B	NM_001278543.2	c.1561C>A	p.Pro521Thr	missense_variant	Exon 13 of 13		NP_001265472.2
C8B	NM_001278544.2	c.1531C>A	p.Pro511Thr	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.1717C>A	p.Pro573Thr	missense_variant	Exon 12 of 12	1	NM_000066.4	ENSP00000360281.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1460786 Hom.: 0 Cov.: 34 AF XY: 0.00000275 AC XY: 2 AN XY: 726692

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: 0.0000166

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Uncertain	0.069	T
BayesDel_noAF	Benign	-0.14
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.50	.;D;.
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	.;D;D
M_CAP	Benign	0.019	T
MetaRNN	Pathogenic	0.85	D;D;D
MetaSVM	Benign	-0.43	T
PrimateAI	Benign	0.38	T
PROVEAN	Pathogenic	-6.9	D;D;D
REVEL	Uncertain	0.44
Sift	Uncertain	0.0030	D;D;D
Sift4G	Uncertain	0.0050	D;D;D
Polyphen		1.0	.;D;D
Vest4		0.82
MutPred		0.60		Gain of phosphorylation at P573 (P = 0.0296);.;.;
MVP		0.69
MPC		0.29
ClinPred		0.99	D
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.77

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: chr1-57395136;