rs730882236

Positions:

• chr13-39699477-A-G

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2 PP3 PP5_Very_Strong

The NM_020751.3(COG6):​c.1167-24A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000002 in 1,000,220 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000020 (0 hom.)
• Consequence: COG6 NM_020751.3 intron
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10
• Conservation: PhyloP100: 0.0340

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]

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 13-39699477-A-G is Pathogenic according to our data. Variant chr13-39699477-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 183333.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-39699477-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COG6	NM_020751.3	c.1167-24A>G		intron_variant		ENST00000455146.8
COG6	NM_001145079.2	c.1167-24A>G		intron_variant
COG6	XM_011535168.2	c.1167-24A>G		intron_variant
COG6	NR_026745.1	n.1332-24A>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COG6	ENST00000455146.8	c.1167-24A>G		intron_variant		1	NM_020751.3	P1
COG6	ENST00000416691.5	c.1167-24A>G		intron_variant		1
COG6	ENST00000356576.8	c.*1004-24A>G		intron_variant, NMD_transcript_variant		1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000200 AC: 2 AN: 1000220 Hom.: 0 Cov.: 13 AF XY: 0.00 AC XY: 0 AN XY: 518504

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000936 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 08, 2022	RT-PCR analysis shows a significant reduction of the normal transcript and the presence of an aberrant COG6 transcript (Shaheen et al., 2013); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 25558065, 23606727, 26260076, 26077850, 29709711, 28600779, 28742265, 31589614, 29878199, 31130284, 32552793, 32860008) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 09, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	May 18, 2022	- -

COG6-congenital disorder of glycosylation Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Centogene AG - the Rare Disease Company	-	- -
Pathogenic, criteria provided, single submitter	research	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 17, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jun 03, 2020	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -

COG6-related disorder Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	Aug 25, 2019	- -
Pathogenic, no assertion criteria provided	clinical testing	PreventionGenetics, part of Exact Sciences	Feb 14, 2024	The COG6 c.1167-24A>G variant is predicted to interfere with splicing. This variant was reported in the homozygous state in individuals with COG6-congenital disorder of glycosylation including hypohidrosis and intellectual disability features (Shaheen et al. 2013. PubMed ID: 23606727; Alsubhi et al. 2017. PubMed ID: 28742265; Monies et al. 2017. PubMed ID: 28600779; Monies et al. 2019. PubMed ID: 31130284; Maddirevula et al. 2020. PubMed ID: 32552793; Bertoli-Avella et al. 2021. PubMed ID: 32860008). This variant was reported as one of the founder variants for congenital disorders of glycosylation in Saudi population (Shaheen et al. 2013. PubMed ID: 23606727; Alsubhi et al. 2017. PubMed ID: 28742265). Functional studies showed this variant largely replaces the canonical acceptor site, resulting in pronounced reduction of the normal transcript and consequent deficiency of COG6 protein (Shaheen et al. 2013. PubMed ID: 23606727). This variant has not been reported in a large population database. This variant is interpreted as pathogenic. -

Hypohidrosis-enamel hypoplasia-palmoplantar keratoderma-intellectual disability syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 01, 2013

- -

Hypohidrosis;C3714756:Intellectual disability Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center

Dec 01, 2014

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	11
DANN	Benign	0.87

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.51		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.51		Position offset: -13
DS_AL_spliceai		0.25		Position offset: 24

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

Publications

LitVar

Other links and lift over

dbSNP: rs730882236; hg19: chr13-40273614;