17-73197386-G-C

Position:

chr17-73197386-G-C

Variant summary

Our verdict is Benign. Variant got -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. 13/20 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

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id is 95920.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1, Benign=2}. Variant chr17-73197386-G-C is described in Lovd as [Likely_benign].

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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COG1	NM_018714.3 linkuse as main transcript	c.903G>C	p.Gln301His	missense_variant	4/14	ENST00000299886.9	NP_061184.1	Q8WTW3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COG1	ENST00000299886.9 linkuse as main transcript	c.903G>C	p.Gln301His	missense_variant	4/14	1	NM_018714.3	ENSP00000299886.4		Q8WTW3
COG1	ENST00000438720.7 linkuse as main transcript	c.900G>C	p.Gln300His	missense_variant	4/13	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

GnomAD3 exomes

AF:

0.00559

AC:

1405

AN:

251376

Hom.:

AF XY:

0.00576

AC XY:

783

AN XY:

135876

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 SAS exome

AF:

0.00314

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

Gnomad4 AFR exome

AF:

0.00155

Gnomad4 AMR exome

AF:

0.00154

Gnomad4 ASJ exome

AF:

0.0192

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.00335

Gnomad4 FIN exome

AF:

0.00714

Gnomad4 NFE exome

AF:

0.00957

Gnomad4 OTH exome

AF:

0.00702

GnomAD4 genome

AF:

0.00517

AC:

787

AN:

152316

Hom.:

Cov.:

AF XY:

0.00482

AC XY:

359

AN XY:

74482

show subpopulations

Gnomad4 AFR

AF:

0.00140

Gnomad4 AMR

AF:

0.00183

Gnomad4 ASJ

AF:

0.0199

Gnomad4 EAS

AF:

0.000386

Gnomad4 SAS

AF:

0.00207

Gnomad4 FIN

AF:

0.00800

Gnomad4 NFE

AF:

0.00764

Gnomad4 OTH

AF:

0.00520

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

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jan 09, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	COG1: BP4, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

COG1 congenital disorder of glycosylation

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	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. -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 11, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Jul 10, 2015	- -

COG1-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 09, 2019

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

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

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

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