rs191156299

Positions:

chr13-39727482-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_020751.3(COG6):c.1760G>A(p.Arg587His) variant causes a missense change. The variant allele was found at a frequency of 0.0000664 in 1,612,298 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 Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000085 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000064 ( 0 hom. )

Consequence

COG6
NM_020751.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 5.70

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:

COG6 (HGNC:):

COG6 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.1982643).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COG6	NM_020751.3 linkuse as main transcript	c.1760G>A	p.Arg587His	missense_variant	18/19	ENST00000455146.8	NP_065802.1	Q9Y2V7-1A0A024RDW5
COG6	NM_001145079.2 linkuse as main transcript	c.1760G>A	p.Arg587His	missense_variant	18/19		NP_001138551.1	Q9Y2V7-2A0A140VJG7
COG6	XM_011535168.2 linkuse as main transcript	c.1760G>A	p.Arg587His	missense_variant	18/20		XP_011533470.1
COG6	NR_026745.1 linkuse as main transcript	n.1925G>A		non_coding_transcript_exon_variant	19/20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
COG6	ENST00000455146.8 linkuse as main transcript	c.1760G>A	p.Arg587His	missense_variant	18/19	1	NM_020751.3	ENSP00000397441.2	Q9Y2V7-1
COG6	ENST00000416691.5 linkuse as main transcript	c.1760G>A	p.Arg587His	missense_variant	18/19	1		ENSP00000403733.1	Q9Y2V7-2
COG6	ENST00000356576.8 linkuse as main transcript	n.*1597G>A		non_coding_transcript_exon_variant	19/20	1		ENSP00000348983.4	Q9Y2V7-4
COG6	ENST00000356576.8 linkuse as main transcript	n.*1597G>A		3_prime_UTR_variant	19/20	1		ENSP00000348983.4	Q9Y2V7-4

Frequencies

GnomAD3 genomes

AF:

0.0000855

AC:

AN:

151972

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000589

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000915

AC:

AN:

251346

Hom.:

AF XY:

0.0000957

AC XY:

AN XY:

135844

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.000992

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.000816

GnomAD4 exome

AF:

0.0000644

AC:

AN:

1460206

Hom.:

Cov.:

AF XY:

0.0000537

AC XY:

AN XY:

726566

show subpopulations

Gnomad4 AFR exome

AF:

0.0000598

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00180

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000464

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000270

Gnomad4 OTH exome

AF:

0.000149

GnomAD4 genome

AF:

0.0000855

AC:

AN:

152092

Hom.:

Cov.:

AF XY:

0.0000673

AC XY:

AN XY:

74344

show subpopulations

Gnomad4 AFR

AF:

0.0000482

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00173

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000589

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000247

Hom.:

Bravo

AF:

0.000132

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000659

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 12, 2024

The c.1760G>A (p.R587H) alteration is located in exon 18 (coding exon 18) of the COG6 gene. This alteration results from a G to A substitution at nucleotide position 1760, causing the arginine (R) at amino acid position 587 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

COG6-congenital disorder of glycosylation

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

COG6-congenital disorder of glycosylation;C3809160:Hypohidrosis-enamel hypoplasia-palmoplantar keratoderma-intellectual disability syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Mar 18, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 540361). This variant has not been reported in the literature in individuals affected with COG6-related conditions. This variant is present in population databases (rs191156299, gnomAD 0.1%). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 587 of the COG6 protein (p.Arg587His). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.076

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Benign

-0.14

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.0092

.;T

Eigen

Uncertain

0.41

Eigen_PC

Uncertain

0.52

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.90

D;D

M_CAP

Benign

0.014

MetaRNN

Benign

0.20

T;T

MetaSVM

Benign

-0.70

MutationAssessor

Uncertain

2.2

M;M

PrimateAI

Uncertain

0.56

PROVEAN

Benign

-1.3

N;N

REVEL

Benign

0.14

Sift

Benign

0.13

T;T

Sift4G

Benign

0.12

T;T

Polyphen

0.0020

.;B

Vest4

0.72

MVP

0.56

MPC

0.064

ClinPred

0.20

GERP RS

5.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.098

gMVP

0.48

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

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