rs121434387

Variant names:

• chr16-69331067-G-C
• rs121434387
• NM_032382.5:c.1611C>G

Your query was ambiguous. Multiple possible variants found:

• chr16-69331067-G-C
• chr16-69331067-G-A

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_032382.5(COG8):​c.1611C>G​(p.Tyr537*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: COG8 NM_032382.5 stop_gained
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 0.322
• Publications: 8 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: Pathogenic. The variant received 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 16-69331067-G-C is Pathogenic according to our data. Variant chr16-69331067-G-C is described in ClinVar as Pathogenic. ClinVar VariationId is 3647.Status of the report is no_assertion_criteria_provided, 0 stars.

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.1611C>G	p.Tyr537*	stop_gained	Exon 5 of 6	NP_115758.3
	COG8	NM_001379261.1		c.1752C>G	p.Tyr584*	stop_gained	Exon 6 of 7	NP_001366190.1
	COG8	NM_001379262.1		c.1611C>G	p.Tyr537*	stop_gained	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.1611C>G	p.Tyr537*	stop_gained	Exon 5 of 6	ENSP00000305459.6	Q96MW5
	ENSG00000272617	ENST00000562949.1	TSL:3	c.352-1888C>G		intron	N/A	ENSP00000457718.1	H3BUN2
	COG8	ENST00000562595.5	TSL:5	c.548+4259C>G		intron	N/A	ENSP00000456705.1	H3BSH5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	COG8-congenital disorder of glycosylation (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	34
DANN	Benign	0.96
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.75
FATHMM_MKL	Benign	0.75	D
PhyloP100		0.32
GERP RS		-4.5
PromoterAI		-0.061	Neutral
Mutation Taster		=60/140	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.33		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.33		Position offset: 28

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs121434387; hg19: chr16-69364970;