13-39655754-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_020751.3(COG6):c.28G>A(p.Ala10Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.414 in 1,591,734 control chromosomes in the GnomAD database, including 140,263 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.44 (15026 hom., cov: 34)
  • Exomes 𝑓: 0.41 (125237 hom.)
• Consequence: COG6 NM_020751.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.101

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.4144059E-5).
• BP6: Variant 13-39655754-G-A is Benign according to our data. Variant chr13-39655754-G-A is described in ClinVar as [Benign]. Clinvar id is 193436.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-39655754-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.574 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COG6	NM_020751.3	c.28G>A	p.Ala10Thr	missense_variant	1/19	ENST00000455146.8
COG6	NM_001145079.2	c.28G>A	p.Ala10Thr	missense_variant	1/19
COG6	XM_011535168.2	c.28G>A	p.Ala10Thr	missense_variant	1/20
COG6	NR_026745.1	n.128G>A		non_coding_transcript_exon_variant	1/20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COG6	ENST00000455146.8	c.28G>A	p.Ala10Thr	missense_variant	1/19	1	NM_020751.3	P1

Frequencies

GnomAD3 genomes AF: 0.439 AC: 66684 AN: 152068 Hom.: 15008 Cov.: 34

Gnomad AFR AF: 0.477

Gnomad AMI AF: 0.459

Gnomad AMR AF: 0.584

Gnomad ASJ AF: 0.459

Gnomad EAS AF: 0.451

Gnomad SAS AF: 0.522

Gnomad FIN AF: 0.362

Gnomad MID AF: 0.513

Gnomad NFE AF: 0.385

Gnomad OTH AF: 0.475

GnomAD3 exomes AF: 0.475 AC: 100290 AN: 210934 Hom.: 24581 AF XY: 0.471 AC XY: 54169 AN XY: 114932

Gnomad AFR exome AF: 0.500

Gnomad AMR exome AF: 0.661

Gnomad ASJ exome AF: 0.475

Gnomad EAS exome AF: 0.449

Gnomad SAS exome AF: 0.553

Gnomad FIN exome AF: 0.375

Gnomad NFE exome AF: 0.409

Gnomad OTH exome AF: 0.463

GnomAD4 exome AF: 0.412 AC: 592562 AN: 1439548 Hom.: 125237 Cov.: 43 AF XY: 0.415 AC XY: 296728 AN XY: 714206

Gnomad4 AFR exome AF: 0.474

Gnomad4 AMR exome AF: 0.649

Gnomad4 ASJ exome AF: 0.474

Gnomad4 EAS exome AF: 0.474

Gnomad4 SAS exome AF: 0.548

Gnomad4 FIN exome AF: 0.370

Gnomad4 NFE exome AF: 0.387

Gnomad4 OTH exome AF: 0.430

GnomAD4 genome AF: 0.439 AC: 66745 AN: 152186 Hom.: 15026 Cov.: 34 AF XY: 0.442 AC XY: 32894 AN XY: 74400

Gnomad4 AFR AF: 0.476

Gnomad4 AMR AF: 0.584

Gnomad4 ASJ AF: 0.459

Gnomad4 EAS AF: 0.450

Gnomad4 SAS AF: 0.523

Gnomad4 FIN AF: 0.362

Gnomad4 NFE AF: 0.385

Gnomad4 OTH AF: 0.480

Alfa AF: 0.402 Hom.: 21465

Bravo AF: 0.456

TwinsUK AF: 0.388 AC: 1438

ALSPAC AF: 0.388 AC: 1494

ESP6500AA AF: 0.494 AC: 2156

ESP6500EA AF: 0.409 AC: 3484

ExAC AF: 0.441 AC: 52046

Asia WGS AF: 0.514 AC: 1786 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 29, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 08, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 14, 2014	- -

COG6-ongenital disorder of glycosylation Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -
Benign, 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

COG6-ongenital disorder of glycosylation;C3809160:Hypohidrosis-enamel hypoplasia-palmoplantar keratoderma-intellectual disability syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

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

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 22, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.60
Cadd	Benign	18
Dann	Uncertain	1.0
Eigen	Benign	-0.78
Eigen_PC	Benign	-0.76
FATHMM_MKL	Benign	0.065	N
LIST_S2	Benign	0.85	T;T;T
MetaRNN	Benign	0.000014	T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Uncertain	2.1	M;M;.
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.44	T
PROVEAN	Benign	0.070	N;N;.
REVEL	Benign	0.029
Sift	Benign	0.18	T;T;.
Sift4G	Benign	0.36	T;T;D
Polyphen		0.0030	.;B;.
Vest4		0.099
MPC		0.054
ClinPred		0.034	T
GERP RS		2.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.067
gMVP		0.36

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: rs3812882; hg19: chr13-40229891; COSMIC: COSV62995992; COSMIC: COSV62995992;