rs12085435

Positions:

• chr1-56949637-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000066.4(C8B):​c.782C>T​(p.Pro261Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0519 in 1,613,678 control chromosomes in the GnomAD database, including 2,456 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.053 (204 hom., cov: 32)
  • Exomes 𝑓: 0.052 (2252 hom.)
• Consequence: C8B NM_000066.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.734

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002777338).
• BP6: Variant 1-56949637-G-A is Benign according to our data. Variant chr1-56949637-G-A is described in ClinVar as [Benign]. Clinvar id is 1170461.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0645 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
C8B	NM_000066.4	c.782C>T	p.Pro261Leu	missense_variant	6/12	ENST00000371237.9	NP_000057.3
C8B	NM_001278543.2	c.626C>T	p.Pro209Leu	missense_variant	7/13		NP_001265472.2
C8B	NM_001278544.2	c.596C>T	p.Pro199Leu	missense_variant	7/13		NP_001265473.2
C8B	XM_047429957.1	c.782C>T	p.Pro261Leu	missense_variant	6/7		XP_047285913.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
C8B	ENST00000371237.9	c.782C>T	p.Pro261Leu	missense_variant	6/12	1	NM_000066.4	ENSP00000360281	P1

Frequencies

GnomAD3 genomes AF: 0.0535 AC: 8127 AN: 151962 Hom.: 204 Cov.: 32

Gnomad AFR AF: 0.0665

Gnomad AMI AF: 0.0219

Gnomad AMR AF: 0.0459

Gnomad ASJ AF: 0.0591

Gnomad EAS AF: 0.000771

Gnomad SAS AF: 0.0632

Gnomad FIN AF: 0.0329

Gnomad MID AF: 0.0665

Gnomad NFE AF: 0.0539

Gnomad OTH AF: 0.0507

GnomAD3 exomes AF: 0.0481 AC: 12072 AN: 251034 Hom.: 335 AF XY: 0.0492 AC XY: 6670 AN XY: 135666

Gnomad AFR exome AF: 0.0655

Gnomad AMR exome AF: 0.0308

Gnomad ASJ exome AF: 0.0548

Gnomad EAS exome AF: 0.000218

Gnomad SAS exome AF: 0.0629

Gnomad FIN exome AF: 0.0329

Gnomad NFE exome AF: 0.0568

Gnomad OTH exome AF: 0.0509

GnomAD4 exome AF: 0.0518 AC: 75673 AN: 1461598 Hom.: 2252 Cov.: 32 AF XY: 0.0522 AC XY: 37956 AN XY: 727122

Gnomad4 AFR exome AF: 0.0654

Gnomad4 AMR exome AF: 0.0316

Gnomad4 ASJ exome AF: 0.0573

Gnomad4 EAS exome AF: 0.000176

Gnomad4 SAS exome AF: 0.0642

Gnomad4 FIN exome AF: 0.0342

Gnomad4 NFE exome AF: 0.0535

Gnomad4 OTH exome AF: 0.0527

GnomAD4 genome AF: 0.0535 AC: 8133 AN: 152080 Hom.: 204 Cov.: 32 AF XY: 0.0526 AC XY: 3913 AN XY: 74332

Gnomad4 AFR AF: 0.0665

Gnomad4 AMR AF: 0.0458

Gnomad4 ASJ AF: 0.0591

Gnomad4 EAS AF: 0.000772

Gnomad4 SAS AF: 0.0631

Gnomad4 FIN AF: 0.0329

Gnomad4 NFE AF: 0.0539

Gnomad4 OTH AF: 0.0501

Alfa AF: 0.0543 Hom.: 483

Bravo AF: 0.0533

TwinsUK AF: 0.0542 AC: 201

ALSPAC AF: 0.0509 AC: 196

ESP6500AA AF: 0.0649 AC: 286

ESP6500EA AF: 0.0556 AC: 478

ExAC AF: 0.0497 AC: 6039

Asia WGS AF: 0.0290 AC: 100 AN: 3478

EpiCase AF: 0.0573

EpiControl AF: 0.0600

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	4.4
DANN	Benign	0.41
DEOGEN2	Benign	0.073	.;T;.
Eigen	Benign	-0.98
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.23	.;T;T
MetaRNN	Benign	0.0028	T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.29	T
PROVEAN	Uncertain	-3.5	D;D;D
REVEL	Benign	0.041
Sift	Benign	0.19	T;T;T
Sift4G	Benign	0.14	T;T;T
Polyphen		0.012, 0.0070	.;B;B
Vest4		0.033
MPC		0.041
ClinPred		0.021	T
GERP RS		0.85
gMVP		0.65

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

LitVar

Other links and lift over

dbSNP: rs12085435; hg19: chr1-57415310;