chr17-73196592-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS1

The NM_018714.3(COG1):c.401C>T(p.Ser134Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000288 in 1,614,186 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. S134S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0011 ( 1 hom., cov: 33)

Exomes 𝑓: 0.00020 ( 1 hom. )

Consequence

COG1
NM_018714.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 3.50

Publications

2 publications found

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 Gene-Disease associations (from GenCC):

COG1-congenital disorder of glycosylation
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, ClinGen, Orphanet

COG1 links:

ENSG00000264860 (HGNC:):

ENSG00000264860 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009982675).

BP6

Variant 17-73196592-C-T is Benign according to our data. Variant chr17-73196592-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 95918.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00111 (169/152296) while in subpopulation AFR AF = 0.00325 (135/41546). AF 95% confidence interval is 0.0028. There are 1 homozygotes in GnomAd4. There are 89 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018714.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COG1	NM_018714.3	MANE Select	c.401C>T	p.Ser134Leu	missense	Exon 2 of 14	NP_061184.1	Q8WTW3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
COG1	ENST00000299886.9	TSL:1 MANE Select	c.401C>T	p.Ser134Leu	missense	Exon 2 of 14	ENSP00000299886.4	Q8WTW3
COG1	ENST00000438720.7	TSL:1	c.398C>T	p.Ser133Leu	missense	Exon 2 of 13	ENSP00000400111.3	E9PBL8
COG1	ENST00000923183.1		c.395C>T	p.Ser132Leu	missense	Exon 2 of 14	ENSP00000593242.1

Frequencies

GnomAD3 genomes

AF:

0.00110

AC:

168

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00323

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00164

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00239

GnomAD2 exomes

AF:

0.000358

AC:

AN:

251492

AF XY:

0.000324

show subpopulations

Gnomad AFR exome

AF:

0.00418

Gnomad AMR exome

AF:

0.000260

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000791

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000202

AC:

296

AN:

1461890

Hom.:

Cov.:

AF XY:

0.000199

AC XY:

145

AN XY:

727246

show subpopulations

African (AFR)

AF:

0.00376

AC:

126

AN:

33480

American (AMR)

AF:

0.000358

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.000520

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000118

AC:

131

AN:

1112012

Other (OTH)

AF:

0.000298

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

105

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome 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

GnomAD4 genome

AF:

0.00111

AC:

169

AN:

152296

Hom.:

Cov.:

AF XY:

0.00119

AC XY:

AN XY:

74482

show subpopulations

African (AFR)

AF:

0.00325

AC:

135

AN:

41546

American (AMR)

AF:

0.00163

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

68034

Other (OTH)

AF:

0.00237

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.513

Heterozygous variant carriers

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:

0.000659

Hom.:

Bravo

AF:

0.00142

ESP6500AA

AF:

0.00431

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000461

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.0000593

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

COG1 congenital disorder of glycosylation (2)

COG1-related disorder (1)

Inborn genetic diseases (1)

not provided (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.39

CADD

Benign

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.026

Eigen

Benign

-0.38

Eigen_PC

Benign

-0.31

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.96

M_CAP

Benign

0.0054

MetaRNN

Benign

0.010

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.9

PhyloP100

3.5

PrimateAI

Benign

0.39

PROVEAN

Uncertain

-2.7

REVEL

Benign

0.096

Sift

Uncertain

0.027

Sift4G

Benign

0.39

Polyphen

0.45

Vest4

0.41

MVP

0.28

MPC

0.11

ClinPred

0.023

GERP RS

2.9

Varity_R

0.11

Mutation Taster

=93/7

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over