rs151318611

Variant names:

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBS1_SupportingBS2

The NM_032382.5(COG8):c.5C>T(p.Ala2Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00114 in 1,608,912 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00085 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0012 ( 4 hom. )

Consequence

COG8
NM_032382.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:6

Conservation

PhyloP100: 1.61

Variant links:

Genes affected

COG8 (HGNC:18623): (component of oligomeric golgi complex 8) This gene encodes a protein that is a component of the conserved oligomeric Golgi (COG) complex, a multiprotein complex that plays a structural role in the Golgi apparatus, and is involved in intracellular membrane trafficking and glycoprotein modification. Mutations in this gene cause congenital disorder of glycosylation, type IIh, a disease that is characterized by under-glycosylated serum proteins, and whose symptoms include severe psychomotor retardation, failure to thrive, seizures, and dairy and wheat product intolerance. [provided by RefSeq, Jul 2008]

COG8 links:

ENSG00000260371 (HGNC:):

ENSG00000260371 links:

NIP7 (HGNC:24328): (nucleolar pre-rRNA processing protein NIP7) Enables RNA binding activity. Predicted to be involved in ribosomal large subunit biogenesis. Located in cytosol; nucleolus; and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

NIP7 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.035721958).

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000847 (129/152330) while in subpopulation NFE AF= 0.00148 (101/68028). AF 95% confidence interval is 0.00125. There are 0 homozygotes in gnomad4. There are 55 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAdExome4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COG8	NM_032382.5 link	c.5C>T	p.Ala2Val	missense_variant	Exon 1 of 6	ENST00000306875.10	NP_115758.3	Q96MW5A0A024R6Z6
NIP7	NM_016101.5 link	c.-282G>A		upstream_gene_variant		ENST00000254940.10	NP_057185.1	Q9Y221-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
COG8	ENST00000306875.10 link	c.5C>T	p.Ala2Val	missense_variant	Exon 1 of 6	1	NM_032382.5	ENSP00000305459.6	Q96MW5B4DYU2
ENSG00000260371	ENST00000563634.1 link	c.3-2836C>T		intron_variant	Intron 1 of 2	4		ENSP00000454500.1	H3BMQ9
ENSG00000259900	ENST00000564737.1 link	n.466-2836C>T		intron_variant	Intron 3 of 4	5		ENSP00000462747.1	J3KT08
NIP7	ENST00000254940.10 link	c.-282G>A		upstream_gene_variant		1	NM_016101.5	ENSP00000254940.5	Q9Y221-1

Frequencies

GnomAD3 genomes

AF:

0.000848

AC:

129

AN:

152212

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000217

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000458

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000753

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00148

Gnomad OTH

AF:

0.000956

GnomAD3 exomes

AF:

0.000831

AC:

205

AN:

246564

Hom.:

AF XY:

0.000910

AC XY:

122

AN XY:

134136

show subpopulations

Gnomad AFR exome

AF:

0.000189

Gnomad AMR exome

AF:

0.000378

Gnomad ASJ exome

AF:

0.000499

Gnomad EAS exome

AF:

0.0000550

Gnomad SAS exome

AF:

0.0000329

Gnomad FIN exome

AF:

0.000930

Gnomad NFE exome

AF:

0.00138

Gnomad OTH exome

AF:

0.00149

GnomAD4 exome

AF:

0.00117

AC:

1705

AN:

1456582

Hom.:

Cov.:

AF XY:

0.00117

AC XY:

850

AN XY:

724770

show subpopulations

Gnomad4 AFR exome

AF:

0.000180

Gnomad4 AMR exome

AF:

0.000514

Gnomad4 ASJ exome

AF:

0.000306

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000813

Gnomad4 FIN exome

AF:

0.000896

Gnomad4 NFE exome

AF:

0.00141

Gnomad4 OTH exome

AF:

0.000731

GnomAD4 genome

AF:

0.000847

AC:

129

AN:

152330

Hom.:

Cov.:

AF XY:

0.000738

AC XY:

AN XY:

74490

show subpopulations

Gnomad4 AFR

AF:

0.000217

Gnomad4 AMR

AF:

0.000457

Gnomad4 ASJ

AF:

0.000576

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000753

Gnomad4 NFE

AF:

0.00148

Gnomad4 OTH

AF:

0.000946

Alfa

AF:

0.00132

Hom.:

Bravo

AF:

0.000703

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00156

AC:

ESP6500AA

AF:

0.000455

AC:

ESP6500EA

AF:

0.00116

AC:

ExAC

AF:

0.000882

AC:

107

EpiCase

AF:

0.00115

EpiControl

AF:

0.00113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:3

May 01, 2017

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 31, 2016

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

COG8-congenital disorder of glycosylation

Uncertain:3

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 2 of the COG8 protein (p.Ala2Val). This variant is present in population databases (rs151318611, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with COG8-related conditions. ClinVar contains an entry for this variant (Variation ID: 377233). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.22

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.20

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.0098

.;T;T

Eigen

Uncertain

0.29

Eigen_PC

Uncertain

0.31

FATHMM_MKL

Benign

0.75

LIST_S2

Benign

0.50

T;T;T

M_CAP

Benign

0.028

MetaRNN

Benign

0.036

T;T;T

MetaSVM

Benign

-0.84

MutationAssessor

Benign

0.69

.;N;.

PrimateAI

Uncertain

0.57

PROVEAN

Benign

0.010

.;.;N

REVEL

Benign

0.12

Sift

Pathogenic

0.0

.;.;D

Sift4G

Benign

0.070

.;.;T

Polyphen

0.98

D;D;.

Vest4

0.53

MVP

0.65

MPC

0.93

ClinPred

0.074

GERP RS

5.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.25

gMVP

0.62

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