7-107298208-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.1247A>G(p.Tyr416Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0062 in 1,613,714 control chromosomes in the GnomAD database, including 43 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 0.0052 ( 4 hom., cov: 32)

Exomes 𝑓: 0.0063 ( 39 hom. )

Consequence

COG5
NM_006348.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.583

Publications

7 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=0.003083676).

BP6

Variant 7-107298208-T-C is Benign according to our data. Variant chr7-107298208-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 194075.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00516 (786/152272) while in subpopulation NFE AF = 0.00798 (543/68014). AF 95% confidence interval is 0.00743. There are 4 homozygotes in GnomAd4. There are 367 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COG5	NM_006348.5 link	c.1247A>G	p.Tyr416Cys	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.1247A>G	p.Tyr416Cys	missense_variant	Exon 12 of 22	1	NM_006348.5	ENSP00000297135.4
COG5	ENST00000347053.8 link	c.1247A>G	p.Tyr416Cys	missense_variant	Exon 12 of 21	1		ENSP00000334703.3
COG5	ENST00000393603.7 link	c.1247A>G	p.Tyr416Cys	missense_variant	Exon 12 of 21	1		ENSP00000377228.3

Frequencies

GnomAD3 genomes

AF:

0.00517

AC:

786

AN:

152154

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00138

Gnomad AMI

AF:

0.0713

Gnomad AMR

AF:

0.00471

Gnomad ASJ

AF:

0.00576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.00113

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00798

Gnomad OTH

AF:

0.00574

GnomAD2 exomes

AF:

0.00474

AC:

1192

AN:

251284

AF XY:

0.00478

show subpopulations

Gnomad AFR exome

AF:

0.00111

Gnomad AMR exome

AF:

0.00515

Gnomad ASJ exome

AF:

0.00506

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00106

Gnomad NFE exome

AF:

0.00767

Gnomad OTH exome

AF:

0.00572

GnomAD4 exome

AF:

0.00631

AC:

9222

AN:

1461442

Hom.:

Cov.:

AF XY:

0.00620

AC XY:

4509

AN XY:

727048

show subpopulations

African (AFR)

AF:

0.00105

AC:

AN:

33468

American (AMR)

AF:

0.00521

AC:

233

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00455

AC:

119

AN:

26126

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39634

South Asian (SAS)

AF:

0.000499

AC:

AN:

86246

European-Finnish (FIN)

AF:

0.00152

AC:

AN:

53398

Middle Eastern (MID)

AF:

0.00642

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.00749

AC:

8331

AN:

1111716

Other (OTH)

AF:

0.00566

AC:

342

AN:

60372

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

409

817

1226

1634

2043

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

302

604

906

1208

1510

<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:

0.00516

AC:

786

AN:

152272

Hom.:

Cov.:

AF XY:

0.00493

AC XY:

367

AN XY:

74470

show subpopulations

African (AFR)

AF:

0.00137

AC:

AN:

41560

American (AMR)

AF:

0.00471

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00576

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.000621

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00113

AC:

AN:

10602

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00798

AC:

543

AN:

68014

Other (OTH)

AF:

0.00568

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

121

161

201

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.00651

Hom.:

Bravo

AF:

0.00506

TwinsUK

AF:

0.00431

AC:

ALSPAC

AF:

0.00934

AC:

ESP6500AA

AF:

0.00113

AC:

ESP6500EA

AF:

0.00512

AC:

ExAC

AF:

0.00458

AC:

556

Asia WGS

AF:

0.000289

AC:

AN:

3476

EpiCase

AF:

0.00884

EpiControl

AF:

0.0107

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

COG5-congenital disorder of glycosylation

Uncertain:1Benign:1

Jan 13, 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. -

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:2

May 05, 2015

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 27, 2016

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided

Benign:2

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 -

Apr 12, 2016

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

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.055

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.54

CADD

Benign

0.044

(source)

DANN

Benign

0.72

DEOGEN2

Benign

0.0066

T;.;.

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.19

LIST_S2

Benign

0.68

T;T;T

MetaRNN

Benign

0.0031

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.0

N;N;N

PhyloP100

-0.58

PrimateAI

Benign

0.31

PROVEAN

Benign

-0.69

N;N;N

REVEL

Benign

0.046

Sift

Benign

0.14

T;T;T

Sift4G

Benign

0.18

T;T;T

Polyphen

0.0

B;B;.

Vest4

0.21

MVP

0.34

MPC

0.065

ClinPred

0.00032

GERP RS

-4.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.052

gMVP

0.38

Mutation Taster

=100/0

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