Genetic Variant COG6:p.His300Asp (chr13-39687612-C-G) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_020751.3(COG6):c.898C>G(p.His300Asp) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H300Y) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 31)

Consequence

COG6
NM_020751.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.63

Publications

4 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.832

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.898C>G	p.His300Asp	missense	Exon 9 of 19	NP_065802.1	Q9Y2V7-1
COG6	NM_001145079.2		c.898C>G	p.His300Asp	missense	Exon 9 of 19	NP_001138551.1	A0A140VJG7
COG6	NR_026745.1		n.1063C>G		non_coding_transcript_exon	Exon 10 of 20

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
COG6	ENST00000455146.8	TSL:1 MANE Select	c.898C>G	p.His300Asp	missense	Exon 9 of 19	ENSP00000397441.2	Q9Y2V7-1
COG6	ENST00000416691.6	TSL:1	c.898C>G	p.His300Asp	missense	Exon 9 of 19	ENSP00000403733.1	Q9Y2V7-2
COG6	ENST00000356576.8	TSL:1	n.*735C>G		non_coding_transcript_exon	Exon 10 of 20	ENSP00000348983.4	Q9Y2V7-4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

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

AlphaMissense

Pathogenic

0.90

BayesDel_addAF

Pathogenic

0.28

BayesDel_noAF

Pathogenic

0.17

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.22

Eigen

Pathogenic

0.68

Eigen_PC

Pathogenic

0.67

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

M_CAP

Benign

0.037

MetaRNN

Pathogenic

0.83

MetaSVM

Benign

-0.52

MutationAssessor

Uncertain

2.4

PhyloP100

5.6

PrimateAI

Pathogenic

0.80

PROVEAN

Pathogenic

-6.0

REVEL

Uncertain

0.42

Sift

Benign

0.10

Sift4G

Uncertain

0.0050

Polyphen

0.96

Vest4

0.93

MutPred

0.57

Gain of catalytic residue at H300 (P = 0.003)

MVP

0.67

MPC

0.37

ClinPred

0.99

GERP RS

5.6

Varity_R

0.76

gMVP

0.70

Mutation Taster

=14/86

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over