NM_006348.5:c.1756C>T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBS1_Supporting

The NM_006348.5(COG5):c.1756C>T(p.His586Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.000184 in 1,562,248 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00076 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00012 ( 1 hom. )

Consequence

COG5
NM_006348.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4B:1

Conservation

PhyloP100: 5.81

Publications

0 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: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.011014938).

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000759 (111/146234) while in subpopulation AFR AF = 0.00263 (104/39520). AF 95% confidence interval is 0.00222. There are 0 homozygotes in GnomAd4. There are 39 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COG5	NM_006348.5 link	c.1756C>T	p.His586Tyr	missense_variant	Exon 17 of 22	ENST00000297135.9	NP_006339.4	Q9UP83

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COG5	ENST00000297135.9 link	c.1756C>T	p.His586Tyr	missense_variant	Exon 17 of 22	1	NM_006348.5	ENSP00000297135.4		Q9UP83

Frequencies

GnomAD3 genomes

AF:

0.000753

AC:

110

AN:

146118

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00261

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000342

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000150

Gnomad OTH

AF:

0.000494

GnomAD2 exomes

AF:

0.000238

AC:

AN:

243846

AF XY:

0.000197

show subpopulations

Gnomad AFR exome

AF:

0.00215

Gnomad AMR exome

AF:

0.000267

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000807

Gnomad OTH exome

AF:

0.000337

GnomAD4 exome

AF:

0.000124

AC:

176

AN:

1416014

Hom.:

Cov.:

AF XY:

0.000123

AC XY:

AN XY:

706418

show subpopulations

African (AFR)

AF:

0.00239

AC:

AN:

32202

American (AMR)

AF:

0.000274

AC:

AN:

43854

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25620

East Asian (EAS)

AF:

0.00

AC:

AN:

39258

South Asian (SAS)

AF:

0.000119

AC:

AN:

84254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50352

Middle Eastern (MID)

AF:

0.00159

AC:

AN:

5666

European-Non Finnish (NFE)

AF:

0.0000390

AC:

AN:

1075960

Other (OTH)

AF:

0.000442

AC:

AN:

58848

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.453

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.000759

AC:

111

AN:

146234

Hom.:

Cov.:

AF XY:

0.000550

AC XY:

AN XY:

70872

show subpopulations

African (AFR)

AF:

0.00263

AC:

104

AN:

39520

American (AMR)

AF:

0.000342

AC:

AN:

14622

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3434

East Asian (EAS)

AF:

0.00

AC:

AN:

5018

South Asian (SAS)

AF:

0.00

AC:

AN:

4636

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8912

Middle Eastern (MID)

AF:

0.00

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.0000150

AC:

AN:

66856

Other (OTH)

AF:

0.000488

AC:

AN:

2048

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

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:

0.000281

Hom.:

ESP6500AA

AF:

0.00136

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000280

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4Benign:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

COG5-congenital disorder of glycosylation

Uncertain:2

Jan 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 617 of the COG5 protein (p.His617Tyr). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with COG5-related conditions. ClinVar contains an entry for this variant (Variation ID: 487322). 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. -

Mar 28, 2022

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Uncertain:1

Sep 26, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: COG5 c.1756C>T (p.His586Tyr) results in a conservative amino acid change in the encoded protein sequence. Three of three in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00024 in 243846 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in COG5 causing Congenital Disorder Of Glycosylation, Type 2i, allowing no conclusion about variant significance. To our knowledge, no occurrence of c.1756C>T in individuals affected with Congenital Disorder Of Glycosylation, Type 2i and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 487322). Based on the evidence outlined above, the variant was classified as uncertain significance. -

not provided

Uncertain:1

Feb 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

COG5: PM2:Supporting, BP4 -

COG5-related disorder

Benign:1

Nov 27, 2023

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

0.070

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.46

CADD

Benign

(source)

DANN

Benign

0.86

DEOGEN2

Benign

0.0034

T;.;.

Eigen

Benign

-0.50

Eigen_PC

Benign

-0.39

FATHMM_MKL

Uncertain

0.87

LIST_S2

Benign

0.64

T;T;T

M_CAP

Benign

0.0095

MetaRNN

Benign

0.011

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.1

L;.;.

PhyloP100

5.8

PrimateAI

Benign

0.48

PROVEAN

Benign

-0.93

N;N;N

REVEL

Benign

0.089

Sift

Benign

0.14

T;T;T

Sift4G

Uncertain

0.034

D;T;T

Polyphen

0.0030

B;B;.

Vest4

0.43

MVP

0.55

MPC

0.061

ClinPred

0.012

GERP RS

4.0

Varity_R

0.053

gMVP

0.32

Mutation Taster

=98/2

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