rs1555277827

Variant names:

• chr13-39699572-T-TA
• rs1555277827
• NM_020751.3:c.1239dupA

Variant summary

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

The ENST00000455146.8(COG6):​c.1239dupA​(p.Phe414IlefsTer4) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. F414F) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: COG6 ENST00000455146.8 frameshift
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 3.79
• Publications: 3 publications found

Genes affected

COG6 (HGNC:18621): (component of oligomeric golgi complex 6) This gene encodes a subunit of the conserved oligomeric Golgi complex that is required for maintaining normal structure and activity of the Golgi apparatus. The encoded protein is organized with conserved oligomeric Golgi complex components 5, 7 and 8 into a sub-complex referred to as lobe B. Alternative splicing results in multiple transcript variants.[provided by RefSeq, Feb 2009]

COG6 Gene-Disease associations (from GenCC):

• COG6-congenital disorder of glycosylation

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: PanelApp Australia, Orphanet, Labcorp Genetics (formerly Invitae)
• hypohidrosis-enamel hypoplasia-palmoplantar keratoderma-intellectual disability syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

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 13-39699572-T-TA is Pathogenic according to our data. Variant chr13-39699572-T-TA is described in ClinVar as Pathogenic. ClinVar VariationId is 493010.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000455146.8. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COG6	NM_020751.3	MANE Select	c.1239dupA	p.Phe414IlefsTer4	frameshift	Exon 13 of 19	NP_065802.1
	COG6	NM_001145079.2		c.1239dupA	p.Phe414IlefsTer4	frameshift	Exon 13 of 19	NP_001138551.1
	COG6	NR_026745.1		n.1404dupA		non_coding_transcript_exon	Exon 14 of 20

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COG6	ENST00000455146.8	TSL:1 MANE Select	c.1239dupA	p.Phe414IlefsTer4	frameshift	Exon 13 of 19	ENSP00000397441.2
	COG6	ENST00000416691.6	TSL:1	c.1239dupA	p.Phe414IlefsTer4	frameshift	Exon 13 of 19	ENSP00000403733.1
	COG6	ENST00000356576.8	TSL:1	n.*1076dupA		non_coding_transcript_exon	Exon 14 of 20	ENSP00000348983.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 25

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	COG6-congenital disorder of glycosylation (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.8
Mutation Taster		=1/199	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: rs1555277827; hg19: chr13-40273709;