16-69331089-G-C

Variant names:

• chr16-69331089-G-C
• rs114861924
• NM_032382.5:c.1589C>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_032382.5(COG8):​c.1589C>G​(p.Pro530Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts 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. P530L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: COG8 NM_032382.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.46
• Publications: 0 publications found

Genes affected

COG8 (HGNC:18623): (component of oligomeric golgi complex 8) This gene encodes a protein that is a component of the conserved oligomeric Golgi (COG) complex, a multiprotein complex that plays a structural role in the Golgi apparatus, and is involved in intracellular membrane trafficking and glycoprotein modification. Mutations in this gene cause congenital disorder of glycosylation, type IIh, a disease that is characterized by under-glycosylated serum proteins, and whose symptoms include severe psychomotor retardation, failure to thrive, seizures, and dairy and wheat product intolerance. [provided by RefSeq, Jul 2008]

COG8 Gene-Disease associations (from GenCC):

• COG8-congenital disorder of glycosylation

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

ENSG00000272617 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.32879055).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032382.5. 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
	COG8	NM_032382.5	MANE Select	c.1589C>G	p.Pro530Arg	missense	Exon 5 of 6	NP_115758.3
	COG8	NM_001379261.1		c.1730C>G	p.Pro577Arg	missense	Exon 6 of 7	NP_001366190.1
	COG8	NM_001379262.1		c.1589C>G	p.Pro530Arg	missense	Exon 5 of 6	NP_001366191.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COG8	ENST00000306875.10	TSL:1 MANE Select	c.1589C>G	p.Pro530Arg	missense	Exon 5 of 6	ENSP00000305459.6	Q96MW5
	ENSG00000272617	ENST00000562949.1	TSL:3	c.352-1910C>G		intron	N/A	ENSP00000457718.1	H3BUN2
	COG8	ENST00000562595.5	TSL:5	c.548+4237C>G		intron	N/A	ENSP00000456705.1	H3BSH5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.024	T
BayesDel_noAF	Benign	-0.27
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.033	T
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.65	T
M_CAP	Benign	0.044	D
MetaRNN	Benign	0.33	T
MetaSVM	Benign	-0.87	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		5.5
PrimateAI	Benign	0.45	T
PROVEAN	Pathogenic	-5.7	D
REVEL	Benign	0.14
Sift	Uncertain	0.0010	D
Polyphen		0.53	P
MutPred		0.35		Loss of glycosylation at P530 (P = 0.0243)
MVP		0.67
MPC		0.15
ClinPred		0.96	D
GERP RS		5.5
Varity_R		0.20
gMVP		0.48

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs114861924; hg19: chr16-69364992;