Variant NM_020751.3:c.1167-24A>G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_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

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11

Conservation

PhyloP100: 0.0340

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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	Effect	Exon rank	MANE	Protein	UniProt
COG6	NM_020751.3 link	c.1167-24A>G	intron_variant	Intron 12 of 18	ENST00000455146.8	NP_065802.1	Q9Y2V7-1A0A024RDW5
COG6	NM_001145079.2 link	c.1167-24A>G	intron_variant	Intron 12 of 18		NP_001138551.1	Q9Y2V7-2A0A140VJG7
COG6	XM_011535168.2 link	c.1167-24A>G	intron_variant	Intron 12 of 19		XP_011533470.1
COG6	NR_026745.1 link	n.1332-24A>G	intron_variant	Intron 13 of 19

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
COG6	ENST00000455146.8 link	c.1167-24A>G	intron_variant	Intron 12 of 18	1	NM_020751.3	ENSP00000397441.2	Q9Y2V7-1
COG6	ENST00000416691.5 link	c.1167-24A>G	intron_variant	Intron 12 of 18	1		ENSP00000403733.1	Q9Y2V7-2
COG6	ENST00000356576.8 link	n.*1004-24A>G	intron_variant	Intron 13 of 19	1		ENSP00000348983.4	Q9Y2V7-4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000200

AC:

AN:

1000220

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

518504

show subpopulations

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.:

Alfa

AF:

0.0000936

Hom.:

Bravo

AF:

0.00000756

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

May 18, 2022

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 08, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) -

Jul 09, 2015

Eurofins Ntd Llc (ga)

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

COG6-congenital disorder of glycosylation

Pathogenic:3

Jun 03, 2020

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -

Mar 17, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Centogene AG - the Rare Disease Company

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

COG6-related disorder

Pathogenic:2

Feb 14, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

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. -

Aug 25, 2019

Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Hypohidrosis-enamel hypoplasia-palmoplantar keratoderma-intellectual disability syndrome

Pathogenic:2

Jul 01, 2013

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Oct 04, 2024

Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

PM3 (very strong), PS3,PM2,PP1 -

Hypohidrosis;C3714756:Intellectual disability

Pathogenic:1

Dec 01, 2014

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.72

CADD

Benign

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over