Genetic Variant COG6:p.Met1? (chr13-39655727-A-C) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PVS1_ModeratePM2

The NM_020751.3(COG6):c.1A>C(p.Met1?) variant causes a initiator codon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000126 in 1,592,862 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 34)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

COG6
NM_020751.3 initiator_codon

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.95

Publications

5 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: Uncertain_significance. The variant received 4 ACMG points.

PVS1

Start lost variant, next in-frame start position is after 2 pathogenic variants. Next in-frame start position is after 53 codons. Genomic position: 39659367. Lost 0.080 part of the original CDS.

PM2

Very rare variant in population databases, with high coverage;

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.1A>C	p.Met1?	initiator_codon	Exon 1 of 19	NP_065802.1	Q9Y2V7-1
COG6	NM_001145079.2		c.1A>C	p.Met1?	initiator_codon	Exon 1 of 19	NP_001138551.1	A0A140VJG7
COG6	NR_026745.1		n.101A>C		non_coding_transcript_exon	Exon 1 of 20

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
COG6	ENST00000455146.8	TSL:1 MANE Select	c.1A>C	p.Met1?	initiator_codon	Exon 1 of 19	ENSP00000397441.2	Q9Y2V7-1
COG6	ENST00000416691.6	TSL:1	c.1A>C	p.Met1?	initiator_codon	Exon 1 of 19	ENSP00000403733.1	Q9Y2V7-2
COG6	ENST00000356576.8	TSL:1	n.1A>C		non_coding_transcript_exon	Exon 1 of 20	ENSP00000348983.4	Q9Y2V7-4

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152242

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

6.94e-7

AC:

AN:

1440620

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

714792

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32936

American (AMR)

AF:

0.00

AC:

AN:

42840

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25696

East Asian (EAS)

AF:

0.0000260

AC:

AN:

38482

South Asian (SAS)

AF:

0.00

AC:

AN:

83566

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51008

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5354

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1101328

Other (OTH)

AF:

0.00

AC:

AN:

59410

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.625

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:

0.00000657

AC:

AN:

152242

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74374

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41466

American (AMR)

AF:

0.00

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5192

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68038

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.625

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:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.33

BayesDel_noAF

Pathogenic

0.23

CADD

Benign

(source)

DANN

Benign

0.88

DEOGEN2

Benign

0.0094

Eigen

Benign

-0.26

Eigen_PC

Benign

-0.14

FATHMM_MKL

Uncertain

0.89

LIST_S2

Uncertain

0.90

M_CAP

Uncertain

0.25

MetaRNN

Pathogenic

0.98

MetaSVM

Benign

-1.1

PhyloP100

3.0

PROVEAN

Benign

-0.48

REVEL

Benign

0.25

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

0.0010

Vest4

0.87

MutPred

0.98

Gain of stability (P = 0.1439)

MVP

0.11

ClinPred

1.0

GERP RS

4.3

PromoterAI

-0.33

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.96

gMVP

0.44

Mutation Taster

=7/193

disease causing

(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