rs191156299

chr13-39727482-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R587C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000085 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000064 (0 hom.)
• Consequence: COG6 NM_020751.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 5.70

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 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	UniProt
COG6	NM_020751.3	c.1760G>A	p.Arg587His	missense_variant	18/19	ENST00000455146.8
COG6	NM_001145079.2	c.1760G>A	p.Arg587His	missense_variant	18/19
COG6	XM_011535168.2	c.1760G>A	p.Arg587His	missense_variant	18/20
COG6	NR_026745.1	n.1925G>A		non_coding_transcript_exon_variant	19/20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COG6	ENST00000455146.8	c.1760G>A	p.Arg587His	missense_variant	18/19	1	NM_020751.3	P1
COG6	ENST00000416691.5	c.1760G>A	p.Arg587His	missense_variant	18/19	1
COG6	ENST00000356576.8	c.*1597G>A		3_prime_UTR_variant, NMD_transcript_variant	19/20	1

Frequencies

GnomAD3 genomes AF: 0.0000855 AC: 13 AN: 151972 Hom.: 0 Cov.: 32

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: 23 AN: 251346 Hom.: 0 AF XY: 0.0000957 AC XY: 13 AN XY: 135844

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: 94 AN: 1460206 Hom.: 0 Cov.: 30 AF XY: 0.0000537 AC XY: 39 AN XY: 726566

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: 13 AN: 152092 Hom.: 0 Cov.: 32 AF XY: 0.0000673 AC XY: 5 AN XY: 74344

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.: 0

Bravo AF: 0.000132

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000659 AC: 8

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

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-ongenital disorder of glycosylation;C3809160:Hypohidrosis-enamel hypoplasia-palmoplantar keratoderma-intellectual disability syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

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). -

COG6-ongenital 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.14
Cadd	Benign	23
Dann	Uncertain	1.0
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D;D
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.20	T;T
MetaSVM	Benign	-0.70	T
MutationAssessor	Uncertain	2.2	M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.56	T
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	T
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

Other links and lift over

dbSNP: rs191156299; hg19: chr13-40301619; COSMIC: COSV62995744;