rs3812883

Positions:

• chr13-39655820-T-A
• chr13-39655820-T-G

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.94T>A​(p.Cys32Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.413 in 1,600,520 control chromosomes in the GnomAD database, including 140,288 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C32F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.44 (15022 hom., cov: 33)
  • Exomes 𝑓: 0.41 (125266 hom.)
• Consequence: COG6 NM_020751.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 2.60

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=1.9721554E-5).
• BP6: Variant 13-39655820-T-A is Benign according to our data. Variant chr13-39655820-T-A is described in ClinVar as [Benign]. Clinvar id is 193437.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-39655820-T-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.94T>A	p.Cys32Ser	missense_variant	1/19	ENST00000455146.8
COG6	NM_001145079.2	c.94T>A	p.Cys32Ser	missense_variant	1/19
COG6	XM_011535168.2	c.94T>A	p.Cys32Ser	missense_variant	1/20
COG6	NR_026745.1	n.194T>A		non_coding_transcript_exon_variant	1/20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COG6	ENST00000455146.8	c.94T>A	p.Cys32Ser	missense_variant	1/19	1	NM_020751.3	P1

Frequencies

GnomAD3 genomes AF: 0.439 AC: 66659 AN: 152014 Hom.: 15004 Cov.: 33

Gnomad AFR AF: 0.476

Gnomad AMI AF: 0.459

Gnomad AMR AF: 0.584

Gnomad ASJ AF: 0.460

Gnomad EAS AF: 0.452

Gnomad SAS AF: 0.523

Gnomad FIN AF: 0.362

Gnomad MID AF: 0.516

Gnomad NFE AF: 0.385

Gnomad OTH AF: 0.475

GnomAD3 exomes AF: 0.458 AC: 104169 AN: 227446 Hom.: 24692 AF XY: 0.455 AC XY: 56353 AN XY: 123936

Gnomad AFR exome AF: 0.473

Gnomad AMR exome AF: 0.651

Gnomad ASJ exome AF: 0.471

Gnomad EAS exome AF: 0.436

Gnomad SAS exome AF: 0.547

Gnomad FIN exome AF: 0.365

Gnomad NFE exome AF: 0.389

Gnomad OTH exome AF: 0.449

GnomAD4 exome AF: 0.411 AC: 594656 AN: 1448386 Hom.: 125266 Cov.: 49 AF XY: 0.414 AC XY: 298060 AN XY: 719562

Gnomad4 AFR exome AF: 0.474

Gnomad4 AMR exome AF: 0.643

Gnomad4 ASJ exome AF: 0.473

Gnomad4 EAS exome AF: 0.472

Gnomad4 SAS exome AF: 0.547

Gnomad4 FIN exome AF: 0.367

Gnomad4 NFE exome AF: 0.386

Gnomad4 OTH exome AF: 0.429

GnomAD4 genome AF: 0.439 AC: 66720 AN: 152134 Hom.: 15022 Cov.: 33 AF XY: 0.442 AC XY: 32888 AN XY: 74382

Gnomad4 AFR AF: 0.476

Gnomad4 AMR AF: 0.584

Gnomad4 ASJ AF: 0.460

Gnomad4 EAS AF: 0.452

Gnomad4 SAS AF: 0.523

Gnomad4 FIN AF: 0.362

Gnomad4 NFE AF: 0.385

Gnomad4 OTH AF: 0.480

Alfa AF: 0.403 Hom.: 9724

Bravo AF: 0.456

TwinsUK AF: 0.388 AC: 1437

ALSPAC AF: 0.387 AC: 1493

ESP6500AA AF: 0.473 AC: 2079

ESP6500EA AF: 0.387 AC: 3324

ExAC AF: 0.434 AC: 52122

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 14, 2014	- -
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	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	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

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 12, 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	0.064
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	13
DANN	Benign	0.58
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.13	T;T;T
MetaRNN	Benign	0.000020	T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	-1.2	N;N;.
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.35	T
PROVEAN	Benign	2.4	N;N;.
REVEL	Benign	0.073
Sift	Benign	0.92	T;T;.
Sift4G	Benign	0.93	T;T;T
Polyphen		0.0	.;B;.
Vest4		0.038
MutPred		0.21		Gain of catalytic residue at T27 (P = 0.002);Gain of catalytic residue at T27 (P = 0.002);Gain of catalytic residue at T27 (P = 0.002);
MPC		0.062
ClinPred		0.0089	T
GERP RS		3.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.063
gMVP		0.11

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: rs3812883; hg19: chr13-40229957; COSMIC: COSV62995068; COSMIC: COSV62995068;