1-56929464-A-G

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The NM_000066.4(C8B):​c.1716T>C​(p.Pro572Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,460,790 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. P572P) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: C8B NM_000066.4 synonymous
• Clinical Significance: Not reported in ClinVar
• 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: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP7: Synonymous conserved (PhyloP=0.241 with no splicing effect.

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>C	p.Pro572Pro	synonymous	Exon 12 of 12	NP_000057.3	P07358
	C8B	NM_001278543.2		c.1560T>C	p.Pro520Pro	synonymous	Exon 13 of 13	NP_001265472.2
	C8B	NM_001278544.2		c.1530T>C	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>C	p.Pro572Pro	synonymous	Exon 12 of 12	ENSP00000360281.4	P07358
	C8B	ENST00000696164.1		c.1716T>C	p.Pro572Pro	synonymous	Exon 13 of 13	ENSP00000512454.1	A0A8Q3WL56
	C8B	ENST00000875298.1		c.1716T>C	p.Pro572Pro	synonymous	Exon 13 of 13	ENSP00000545357.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000797 AC: 2 AN: 251066 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1460790 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 726706

African (AFR) AF: 0.00 AC: 0 AN: 33432

American (AMR) AF: 0.0000224 AC: 1 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.000115 AC: 3 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: 0.00 AC: 0 AN: 53420

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

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111902

Other (OTH) AF: 0.0000332 AC: 2 AN: 60292

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	7.4
DANN	Benign	0.74
PhyloP100		0.24
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;