NM_000066.4:c.1716T>G

Variant names:

• chr1-56929464-A-C
• rs149900569
• NM_000066.4:c.1716T>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Very_Strong BP7 BS2_Supporting

The NM_000066.4(C8B):​c.1716T>G​(p.Pro572Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00132 in 1,613,074 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00068 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0014 (2 hom.)
• Consequence: C8B NM_000066.4 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.241
• Publications: 0 publications found

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]

C8B Gene-Disease associations (from GenCC):

• type II complement component 8 deficiency

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.59).
• BP6: Variant 1-56929464-A-C is Benign according to our data. Variant chr1-56929464-A-C is described in ClinVar as Likely_benign. ClinVar VariationId is 1131461.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.241 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000066.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C8B	NM_000066.4	MANE Select	c.1716T>G	p.Pro572Pro	synonymous	Exon 12 of 12	NP_000057.3	P07358
	C8B	NM_001278543.2		c.1560T>G	p.Pro520Pro	synonymous	Exon 13 of 13	NP_001265472.2
	C8B	NM_001278544.2		c.1530T>G	p.Pro510Pro	synonymous	Exon 13 of 13	NP_001265473.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C8B	ENST00000371237.9	TSL:1 MANE Select	c.1716T>G	p.Pro572Pro	synonymous	Exon 12 of 12	ENSP00000360281.4	P07358
	C8B	ENST00000696164.1		c.1716T>G	p.Pro572Pro	synonymous	Exon 13 of 13	ENSP00000512454.1	A0A8Q3WL56
	C8B	ENST00000875298.1		c.1716T>G	p.Pro572Pro	synonymous	Exon 13 of 13	ENSP00000545357.1

Frequencies

GnomAD3 genomes AF: 0.000677 AC: 103 AN: 152166 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00129

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000558 AC: 140 AN: 251066 AF XY: 0.000553

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.000434

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000996

Gnomad OTH exome AF: 0.000978

GnomAD4 exome AF: 0.00139 AC: 2028 AN: 1460790 Hom.: 2 Cov.: 33 AF XY: 0.00132 AC XY: 959 AN XY: 726706

African (AFR) AF: 0.000269 AC: 9 AN: 33432

American (AMR) AF: 0.000380 AC: 17 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86200

European-Finnish (FIN) AF: 0.0000749 AC: 4 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5016

European-Non Finnish (NFE) AF: 0.00172 AC: 1917 AN: 1111902

Other (OTH) AF: 0.00134 AC: 81 AN: 60292

GnomAD4 genome AF: 0.000676 AC: 103 AN: 152284 Hom.: 0 Cov.: 33 AF XY: 0.000443 AC XY: 33 AN XY: 74454

African (AFR) AF: 0.000313 AC: 13 AN: 41582

American (AMR) AF: 0.0000654 AC: 1 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00129 AC: 88 AN: 68016

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.000916 Hom.: 0

Bravo AF: 0.000676

EpiCase AF: 0.00104

EpiControl AF: 0.000771

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	6.7
DANN	Benign	0.74
PhyloP100		0.24
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs149900569; hg19: chr1-57395137;