13-39682261-A-G

Variant names:

• chr13-39682261-A-G
• rs756826030
• NM_020751.3:c.785A>G

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Moderate PP5_Moderate

The NM_020751.3(COG6):​c.785A>G​(p.Tyr262Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000083 in 1,446,170 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 Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y262H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000083 (0 hom.)
• Consequence: COG6 NM_020751.3 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 5.40
• Publications: 7 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 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 13-39682261-A-G is Pathogenic according to our data. Variant chr13-39682261-A-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 493009.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COG6	NM_020751.3	c.785A>G	p.Tyr262Cys	missense_variant	Exon 8 of 19	ENST00000455146.8	NP_065802.1
COG6	NM_001145079.2	c.785A>G	p.Tyr262Cys	missense_variant	Exon 8 of 19		NP_001138551.1
COG6	XM_011535168.2	c.785A>G	p.Tyr262Cys	missense_variant	Exon 8 of 20		XP_011533470.1
COG6	NR_026745.1	n.950A>G		non_coding_transcript_exon_variant	Exon 9 of 20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COG6	ENST00000455146.8	c.785A>G	p.Tyr262Cys	missense_variant	Exon 8 of 19	1	NM_020751.3	ENSP00000397441.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000399 AC: 1 AN: 250382 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000291

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000830 AC: 12 AN: 1446170 Hom.: 0 Cov.: 26 AF XY: 0.00000972 AC XY: 7 AN XY: 720344

African (AFR) AF: 0.00 AC: 0 AN: 33138

American (AMR) AF: 0.0000448 AC: 2 AN: 44626

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26018

East Asian (EAS) AF: 0.00 AC: 0 AN: 39526

South Asian (SAS) AF: 0.0000234 AC: 2 AN: 85550

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53382

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5736

European-Non Finnish (NFE) AF: 0.00000728 AC: 8 AN: 1098324

Other (OTH) AF: 0.00 AC: 0 AN: 59870

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Sep 20, 2024

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analyses support that this missense variant has a deleterious effect on protein structure/function and on splicing; This variant is associated with the following publications: (PMID: 31589614, 33726816, 36636598, 34940998, 26260076) -

COG6-congenital disorder of glycosylation Pathogenic:1

Sep 15, 2010

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Pathogenic	0.17
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Benign	0.17	.;T
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D;D
M_CAP	Benign	0.044	D
MetaRNN	Pathogenic	0.87	D;D
MetaSVM	Benign	-0.59	T
MutationAssessor	Uncertain	2.0	M;M
PhyloP100		5.4
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-5.0	D;D
REVEL	Uncertain	0.52
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.0020	D;D
Polyphen		1.0	.;D
Vest4		0.97
MutPred		0.69		Gain of methylation at K263 (P = 0.0172);Gain of methylation at K263 (P = 0.0172);
MVP		0.70
MPC		0.36
ClinPred		0.99	D
GERP RS		5.7
Varity_R		0.61
gMVP		0.58
Mutation Taster		=4/96	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_DG_spliceai		1.0		Position offset: -1
DS_DL_spliceai		0.92		Position offset: 3

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

Other links and lift over

dbSNP: rs756826030; hg19: chr13-40256398;