13-39723394-G-T

Variant names:

• chr13-39723394-G-T
• rs387906959
• NM_020751.3:c.1646G>T

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_020751.3(COG6):​c.1646G>T​(p.Gly549Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,106 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G549C) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: COG6 NM_020751.3 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:4
• Conservation: PhyloP100: 7.50
• Publications: 17 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: Likely_pathogenic. The variant received 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.942
• PP5: Variant 13-39723394-G-T is Pathogenic according to our data. Variant chr13-39723394-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 30628.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COG6	NM_020751.3	c.1646G>T	p.Gly549Val	missense_variant	Exon 16 of 19	ENST00000455146.8	NP_065802.1
COG6	NM_001145079.2	c.1646G>T	p.Gly549Val	missense_variant	Exon 16 of 19		NP_001138551.1
COG6	XM_011535168.2	c.1646G>T	p.Gly549Val	missense_variant	Exon 16 of 20		XP_011533470.1
COG6	NR_026745.1	n.1811G>T		non_coding_transcript_exon_variant	Exon 17 of 20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COG6	ENST00000455146.8	c.1646G>T	p.Gly549Val	missense_variant	Exon 16 of 19	1	NM_020751.3	ENSP00000397441.2
COG6	ENST00000416691.6	c.1646G>T	p.Gly549Val	missense_variant	Exon 16 of 19	1		ENSP00000403733.1
COG6	ENST00000356576.8	n.*1483G>T		non_coding_transcript_exon_variant	Exon 17 of 20	1		ENSP00000348983.4
COG6	ENST00000356576.8	n.*1483G>T		3_prime_UTR_variant	Exon 17 of 20	1		ENSP00000348983.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459106 Hom.: 0 Cov.: 28 AF XY: 0.00000138 AC XY: 1 AN XY: 726014

African (AFR) AF: 0.00 AC: 0 AN: 33398

American (AMR) AF: 0.00 AC: 0 AN: 44632

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26088

East Asian (EAS) AF: 0.00 AC: 0 AN: 39642

South Asian (SAS) AF: 0.00 AC: 0 AN: 86196

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53342

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5754

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1109770

Other (OTH) AF: 0.0000166 AC: 1 AN: 60284

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000369 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:2

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

COG6-congenital disorder of glycosylation Pathogenic:2

Jul 01, 2013

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Sep 12, 2023

Laboratoire Génétique Moléculaire, CHRU TOURS

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS2;PM2;PM3;PP3;PP5

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.72
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.30
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0	.;T
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Uncertain	0.088	D
MetaRNN	Pathogenic	0.94	D;D
MetaSVM	Uncertain	0.34	D
MutationAssessor	Pathogenic	3.1	M;M
PhyloP100		7.5
PrimateAI	Uncertain	0.70	T
PROVEAN	Pathogenic	-6.7	D;D
REVEL	Pathogenic	0.81
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.0040	D;D
Vest4		0.93
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.91
gMVP		0.84
Mutation Taster		=21/79	disease causing (ClinVar)

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: rs387906959; hg19: chr13-40297531;