rs374488082

Variant names:

• chr17-79795356-C-A
• rs374488082
• NM_020649.3:c.449G>T

Your query was ambiguous. Multiple possible variants found:

• chr17-79795356-C-A
• chr17-79795356-C-G
• chr17-79795356-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_020649.3(CBX8):​c.449G>T​(p.Arg150Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000119 in 1,591,536 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R150Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000090 (0 hom.)
• Consequence: CBX8 NM_020649.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.262
• Publications: 1 publications found

Genes affected

CBX8 (HGNC:15962): (chromobox 8) Enables methylated histone binding activity. Involved in negative regulation of transcription by RNA polymerase II. Located in chromatin and nucleoplasm. Part of PRC1 complex. Biomarker of esophagus squamous cell carcinoma and glioblastoma. [provided by Alliance of Genome Resources, Apr 2022]

CBX8 Gene-Disease associations (from GenCC):

• schizophrenia

  Inheritance: Unknown Classification: NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16426548).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020649.3. 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
	CBX8	NM_020649.3	MANE Select	c.449G>T	p.Arg150Leu	missense	Exon 5 of 5	NP_065700.1	Q9HC52

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CBX8	ENST00000269385.9	TSL:1 MANE Select	c.449G>T	p.Arg150Leu	missense	Exon 5 of 5	ENSP00000269385.4	Q9HC52
	CBX8	ENST00000413392.5	TSL:3	c.419G>T	p.Arg140Leu	missense	Exon 5 of 5	ENSP00000405058.1	C9J6K3
	CBX8	ENST00000427800.2	TSL:2	c.374G>T	p.Arg125Leu	missense	Exon 5 of 5	ENSP00000408753.2	C9JM54

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152234 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000235 AC: 5 AN: 212674 AF XY: 0.00000875

Gnomad AFR exome AF: 0.0000743

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000167

Gnomad NFE exome AF: 0.0000106

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000903 AC: 13 AN: 1439302 Hom.: 0 Cov.: 35 AF XY: 0.00000560 AC XY: 4 AN XY: 714072

African (AFR) AF: 0.00 AC: 0 AN: 33240

American (AMR) AF: 0.00 AC: 0 AN: 40258

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25528

East Asian (EAS) AF: 0.00 AC: 0 AN: 38822

South Asian (SAS) AF: 0.00 AC: 0 AN: 83506

European-Finnish (FIN) AF: 0.000137 AC: 7 AN: 51144

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5740

European-Non Finnish (NFE) AF: 0.00000545 AC: 6 AN: 1101372

Other (OTH) AF: 0.00 AC: 0 AN: 59692

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152234 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74368

African (AFR) AF: 0.0000241 AC: 1 AN: 41470

American (AMR) AF: 0.00 AC: 0 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68042

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000476 Hom.: 0

Bravo AF: 0.0000151

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00000826 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.10	T
Eigen	Benign	0.078
Eigen_PC	Benign	0.14
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.64	T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-0.80	T
MutationAssessor	Benign	0.76	N
PhyloP100		0.26
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-0.68	N
REVEL	Benign	0.23
Sift	Benign	0.13	T
Sift4G	Benign	0.11	T
Polyphen		0.84	P
Vest4		0.15
MVP		0.65
MPC		0.26
ClinPred		0.060	T
GERP RS		4.5
Varity_R		0.083
gMVP		0.27
Mutation Taster		=68/32	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: rs374488082; hg19: chr17-77769155;