17-73197386-G-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_018714.3(COG1):c.903G>C(p.Gln301His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00815 in 1,614,104 control chromosomes in the GnomAD database, including 67 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0052 ( 2 hom., cov: 33)

Exomes 𝑓: 0.0085 ( 65 hom. )

Consequence

COG1
NM_018714.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:8

Conservation

PhyloP100: 1.25

Publications

12 publications found

Variant links:

Genes affected

COG1 (HGNC:6545): (component of oligomeric golgi complex 1) The protein encoded by this gene is one of eight proteins (Cog1-8) which form a Golgi-localized complex (COG) required for normal Golgi morphology and function. It is thought that this protein is required for steps in the normal medial and trans Golgi-associated processing of glycoconjugates and plays a role in the organization of the Golgi-localized complex. [provided by RefSeq, Jul 2008]

COG1 Gene-Disease associations (from GenCC):

COG1-congenital disorder of glycosylation
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, G2P, PanelApp Australia, ClinGen

COG1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.003544867).

BP6

Variant 17-73197386-G-C is Benign according to our data. Variant chr17-73197386-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 95920.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00517 (787/152316) while in subpopulation NFE AF = 0.00764 (520/68038). AF 95% confidence interval is 0.0071. There are 2 homozygotes in GnomAd4. There are 359 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COG1	NM_018714.3 link	c.903G>C	p.Gln301His	missense_variant	Exon 4 of 14	ENST00000299886.9	NP_061184.1	Q8WTW3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COG1	ENST00000299886.9 link	c.903G>C	p.Gln301His	missense_variant	Exon 4 of 14	1	NM_018714.3	ENSP00000299886.4		Q8WTW3
COG1	ENST00000438720.7 link	c.900G>C	p.Gln300His	missense_variant	Exon 4 of 13	1		ENSP00000400111.3		E9PBL8

Frequencies

GnomAD3 genomes

AF:

0.00518

AC:

788

AN:

152198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00140

Gnomad AMI

AF:

0.00439

Gnomad AMR

AF:

0.00183

Gnomad ASJ

AF:

0.0199

Gnomad EAS

AF:

0.000386

Gnomad SAS

AF:

0.00228

Gnomad FIN

AF:

0.00800

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00764

Gnomad OTH

AF:

0.00526

GnomAD2 exomes

AF:

0.00559

AC:

1405

AN:

251376

AF XY:

0.00576

show subpopulations

Gnomad AFR exome

AF:

0.00142

Gnomad AMR exome

AF:

0.00130

Gnomad ASJ exome

AF:

0.0177

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00686

Gnomad NFE exome

AF:

0.00781

Gnomad OTH exome

AF:

0.00440

GnomAD4 exome

AF:

0.00846

AC:

12365

AN:

1461788

Hom.:

Cov.:

AF XY:

0.00829

AC XY:

6029

AN XY:

727206

show subpopulations

African (AFR)

AF:

0.00155

AC:

AN:

33480

American (AMR)

AF:

0.00154

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0192

AC:

502

AN:

26136

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39700

South Asian (SAS)

AF:

0.00335

AC:

289

AN:

86258

European-Finnish (FIN)

AF:

0.00714

AC:

381

AN:

53332

Middle Eastern (MID)

AF:

0.000520

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00957

AC:

10643

AN:

1111996

Other (OTH)

AF:

0.00702

AC:

424

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

686

1372

2058

2744

3430

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

440

880

1320

1760

2200

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00517

AC:

787

AN:

152316

Hom.:

Cov.:

AF XY:

0.00482

AC XY:

359

AN XY:

74482

show subpopulations

African (AFR)

AF:

0.00140

AC:

AN:

41566

American (AMR)

AF:

0.00183

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.0199

AC:

AN:

3472

East Asian (EAS)

AF:

0.000386

AC:

AN:

5176

South Asian (SAS)

AF:

0.00207

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00800

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00764

AC:

520

AN:

68038

Other (OTH)

AF:

0.00520

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

133

178

222

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00566

Hom.:

Bravo

AF:

0.00456

TwinsUK

AF:

0.00944

AC:

ALSPAC

AF:

0.0101

AC:

ESP6500AA

AF:

0.00136

AC:

ESP6500EA

AF:

0.00826

AC:

ExAC

AF:

0.00529

AC:

642

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.00752

EpiControl

AF:

0.00765

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:8

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:4

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 09, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

COG1: BP4, BS2 -

COG1 congenital disorder of glycosylation

Uncertain:1Benign:1

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

not specified

Benign:2

Oct 11, 2016

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 10, 2015

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

COG1-related disorder

Benign:1

Jul 09, 2019

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.50

CADD

Benign

(source)

DANN

Benign

0.92

DEOGEN2

Benign

0.031

T;T

Eigen

Uncertain

0.20

Eigen_PC

Benign

0.13

FATHMM_MKL

Uncertain

0.76

LIST_S2

Benign

0.72

T;T

M_CAP

Benign

0.0066

MetaRNN

Benign

0.0035

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.6

.;M

PhyloP100

1.2

PrimateAI

Benign

0.36

PROVEAN

Benign

-2.1

.;N

REVEL

Benign

0.076

Sift

Benign

0.037

.;D

Sift4G

Benign

0.096

T;T

Polyphen

0.96

.;D

Vest4

0.16

MutPred

0.20

Gain of methylation at K306 (P = 0.1636);Gain of methylation at K306 (P = 0.1636);

MVP

0.36

MPC

0.098

ClinPred

0.011

GERP RS

3.3

Varity_R

0.067

Mutation Taster

=99/1

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over