7-107298193-T-C

Variant names:

Variant summary

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

The NM_006348.5(COG5):c.1262A>G(p.His421Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00383 in 1,613,208 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 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 0.0028 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0039 ( 21 hom. )

Consequence

COG5
NM_006348.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:5

Conservation

PhyloP100: 1.86

Publications

12 publications found

Variant links:

Genes affected

COG5 (HGNC:14857): (component of oligomeric golgi complex 5) 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. The encoded protein is organized with conserved oligomeric Golgi complex components 6, 7 and 8 into a sub-complex referred to as lobe B. Alternative splicing results in multiple transcript variants. Mutations in this gene result in congenital disorder of glycosylation type 2I.[provided by RefSeq, Jan 2011]

COG5 Gene-Disease associations (from GenCC):

COG5-congenital disorder of glycosylation
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, Laboratory for Molecular Medicine, Orphanet, G2P

COG5 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=0.0037671328).

BP6

Variant 7-107298193-T-C is Benign according to our data. Variant chr7-107298193-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 358461.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00281 (428/152302) while in subpopulation NFE AF = 0.00463 (315/68006). AF 95% confidence interval is 0.00421. There are 0 homozygotes in GnomAd4. There are 196 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 21 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COG5	NM_006348.5 link	c.1262A>G	p.His421Arg	missense_variant	Exon 12 of 22	ENST00000297135.9	NP_006339.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
COG5	ENST00000297135.9 link	c.1262A>G	p.His421Arg	missense_variant	Exon 12 of 22	1	NM_006348.5	ENSP00000297135.4
COG5	ENST00000347053.8 link	c.1262A>G	p.His421Arg	missense_variant	Exon 12 of 21	1		ENSP00000334703.3
COG5	ENST00000393603.7 link	c.1262A>G	p.His421Arg	missense_variant	Exon 12 of 21	1		ENSP00000377228.3

Frequencies

GnomAD3 genomes

AF:

0.00281

AC:

427

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000579

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00268

Gnomad ASJ

AF:

0.00374

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00414

Gnomad FIN

AF:

0.000377

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.00462

Gnomad OTH

AF:

0.00383

GnomAD2 exomes

AF:

0.00347

AC:

873

AN:

251248

AF XY:

0.00389

show subpopulations

Gnomad AFR exome

AF:

0.000677

Gnomad AMR exome

AF:

0.00243

Gnomad ASJ exome

AF:

0.00298

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000832

Gnomad NFE exome

AF:

0.00492

Gnomad OTH exome

AF:

0.00555

GnomAD4 exome

AF:

0.00394

AC:

5758

AN:

1460906

Hom.:

Cov.:

AF XY:

0.00410

AC XY:

2978

AN XY:

726736

show subpopulations

African (AFR)

AF:

0.000478

AC:

AN:

33450

American (AMR)

AF:

0.00244

AC:

109

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.00310

AC:

AN:

26098

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39620

South Asian (SAS)

AF:

0.00488

AC:

420

AN:

86122

European-Finnish (FIN)

AF:

0.00137

AC:

AN:

53360

Middle Eastern (MID)

AF:

0.0184

AC:

106

AN:

5754

European-Non Finnish (NFE)

AF:

0.00419

AC:

4660

AN:

1111442

Other (OTH)

AF:

0.00484

AC:

292

AN:

60348

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

249

498

748

997

1246

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

164

328

492

656

820

<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:

0.00281

AC:

428

AN:

152302

Hom.:

Cov.:

AF XY:

0.00263

AC XY:

196

AN XY:

74482

show subpopulations

African (AFR)

AF:

0.000577

AC:

AN:

41584

American (AMR)

AF:

0.00268

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00374

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00415

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.000377

AC:

AN:

10604

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00463

AC:

315

AN:

68006

Other (OTH)

AF:

0.00379

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

114

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00394

Hom.:

Bravo

AF:

0.00296

TwinsUK

AF:

0.00297

AC:

ALSPAC

AF:

0.00467

AC:

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.00430

AC:

ExAC

AF:

0.00344

AC:

417

Asia WGS

AF:

0.000867

AC:

AN:

3476

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:3

Sep 06, 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

Sep 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

COG5: BP4, BS2

Jul 06, 2018

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

COG5-congenital disorder of glycosylation

Uncertain:1Benign:1

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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.

COG5-related disorder

Benign:1

May 20, 2022

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

0.073

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.51

CADD

Benign

(source)

DANN

Benign

0.66

DEOGEN2

Benign

0.0043

T;.;.

Eigen

Benign

-0.79

Eigen_PC

Benign

-0.70

FATHMM_MKL

Benign

0.44

LIST_S2

Benign

0.63

T;T;T

MetaRNN

Benign

0.0038

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.90

L;L;L

PhyloP100

1.9

PrimateAI

Benign

0.37

PROVEAN

Benign

-0.68

N;N;N

REVEL

Benign

0.043

Sift

Benign

0.34

T;T;T

Sift4G

Benign

0.37

T;T;T

Vest4

0.31

ClinPred

0.0048

GERP RS

4.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.043

gMVP

0.28

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