Genetic Variant COG6:p.Asn394Asp (chr13-39699514-A-G) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_020751.3(COG6):c.1180A>G(p.Asn394Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000523 in 1,561,924 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0030 ( 2 hom., cov: 32)

Exomes 𝑓: 0.00025 ( 0 hom. )

Consequence

COG6
NM_020751.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 8.85

Publications

0 publications found

Variant links:

Genes affected

COG6 (HGNC:18621): (component of oligomeric golgi complex 6) This gene encodes a subunit of the conserved oligomeric Golgi complex that is required for maintaining normal structure and activity of the Golgi apparatus. The encoded protein is organized with conserved oligomeric Golgi complex components 5, 7 and 8 into a sub-complex referred to as lobe B. Alternative splicing results in multiple transcript variants.[provided by RefSeq, Feb 2009]

COG6 Gene-Disease associations (from GenCC):

COG6-congenital disorder of glycosylation
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Orphanet
hypohidrosis-enamel hypoplasia-palmoplantar keratoderma-intellectual disability syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

COG6 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009499133).

BP6

Variant 13-39699514-A-G is Benign according to our data. Variant chr13-39699514-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 235506.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00305 (463/151974) while in subpopulation AFR AF = 0.0108 (450/41516). AF 95% confidence interval is 0.01. There are 2 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 GnomAd4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020751.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
COG6	NM_020751.3	MANE Select	c.1180A>G	p.Asn394Asp	missense	Exon 13 of 19	NP_065802.1	Q9Y2V7-1
COG6	NM_001145079.2		c.1180A>G	p.Asn394Asp	missense	Exon 13 of 19	NP_001138551.1	A0A140VJG7
COG6	NR_026745.1		n.1345A>G		non_coding_transcript_exon	Exon 14 of 20

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
COG6	ENST00000455146.8	TSL:1 MANE Select	c.1180A>G	p.Asn394Asp	missense	Exon 13 of 19	ENSP00000397441.2	Q9Y2V7-1
COG6	ENST00000416691.6	TSL:1	c.1180A>G	p.Asn394Asp	missense	Exon 13 of 19	ENSP00000403733.1	Q9Y2V7-2
COG6	ENST00000356576.8	TSL:1	n.*1017A>G		non_coding_transcript_exon	Exon 14 of 20	ENSP00000348983.4	Q9Y2V7-4

Frequencies

GnomAD3 genomes

AF:

0.00305

AC:

463

AN:

151856

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0109

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000723

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:

0.00

Gnomad OTH

AF:

0.000956

GnomAD2 exomes

AF:

0.000630

AC:

157

AN:

249312

AF XY:

0.000445

show subpopulations

Gnomad AFR exome

AF:

0.00949

Gnomad AMR exome

AF:

0.0000877

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000165

GnomAD4 exome

AF:

0.000251

AC:

354

AN:

1409950

Hom.:

Cov.:

AF XY:

0.000210

AC XY:

148

AN XY:

704710

show subpopulations

African (AFR)

AF:

0.00950

AC:

308

AN:

32412

American (AMR)

AF:

0.000113

AC:

AN:

44392

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25668

East Asian (EAS)

AF:

0.00

AC:

AN:

39226

South Asian (SAS)

AF:

0.00

AC:

AN:

85054

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53254

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5604

European-Non Finnish (NFE)

AF:

0.00000188

AC:

AN:

1065910

Other (OTH)

AF:

0.000667

AC:

AN:

58430

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.452

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<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:

0.00305

AC:

463

AN:

151974

Hom.:

Cov.:

AF XY:

0.00264

AC XY:

196

AN XY:

74296

show subpopulations

African (AFR)

AF:

0.0108

AC:

450

AN:

41516

American (AMR)

AF:

0.000722

AC:

AN:

15228

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3462

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67836

Other (OTH)

AF:

0.000946

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

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:

0.000467

Hom.:

Bravo

AF:

0.00325

ESP6500AA

AF:

0.0104

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000899

AC:

109

Asia WGS

AF:

0.000579

AC:

AN:

3468

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

COG6-congenital disorder of glycosylation;C3809160:Hypohidrosis-enamel hypoplasia-palmoplantar keratoderma-intellectual disability syndrome (2)

COG6-congenital disorder of glycosylation (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.065

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.60

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.0037

Eigen

Benign

-0.16

Eigen_PC

Benign

0.090

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.84

MetaRNN

Benign

0.0095

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.68

PhyloP100

8.8

PrimateAI

Uncertain

0.69

PROVEAN

Benign

-0.67

REVEL

Benign

0.12

Sift

Benign

0.64

Sift4G

Benign

0.67

Polyphen

0.0

Vest4

0.52

MVP

0.35

MPC

0.059

ClinPred

0.068

GERP RS

5.3

Varity_R

0.24

gMVP

0.29

Mutation Taster

=95/5

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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