Genetic Variant COG6:p.Ser12Thr (chr13-39655760-T-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_020751.3(COG6):c.34T>A(p.Ser12Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S12C) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

COG6
NM_020751.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.291

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: STRONG, SUPPORTIVE Submitted by: PanelApp Australia, Orphanet, Labcorp Genetics (formerly Invitae)
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: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.056364447).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COG6	NM_020751.3 link	c.34T>A	p.Ser12Thr	missense_variant	Exon 1 of 19	ENST00000455146.8	NP_065802.1	Q9Y2V7-1A0A024RDW5
COG6	NM_001145079.2 link	c.34T>A	p.Ser12Thr	missense_variant	Exon 1 of 19		NP_001138551.1	Q9Y2V7-2A0A140VJG7
COG6	XM_011535168.2 link	c.34T>A	p.Ser12Thr	missense_variant	Exon 1 of 20		XP_011533470.1
COG6	NR_026745.1 link	n.134T>A		non_coding_transcript_exon_variant	Exon 1 of 20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COG6	ENST00000455146.8 link	c.34T>A	p.Ser12Thr	missense_variant	Exon 1 of 19	1	NM_020751.3	ENSP00000397441.2		Q9Y2V7-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

1441100

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

715096

African (AFR)

AF:

0.00

AC:

AN:

32942

American (AMR)

AF:

0.00

AC:

AN:

42940

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25794

East Asian (EAS)

AF:

0.00

AC:

AN:

38436

South Asian (SAS)

AF:

0.00

AC:

AN:

83652

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50742

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4958

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1102198

Other (OTH)

AF:

0.00

AC:

AN:

59438

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Sep 22, 2021

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.34T>A (p.S12T) alteration is located in exon 1 (coding exon 1) of the COG6 gene. This alteration results from a T to A substitution at nucleotide position 34, causing the serine (S) at amino acid position 12 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.067

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.68

CADD

Benign

6.0

(source)

DANN

Benign

0.92

DEOGEN2

Benign

0.0086

.;T;T

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.72

T;T;T

M_CAP

Benign

0.0071

MetaRNN

Benign

0.056

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.55

N;N;.

PhyloP100

-0.29

PrimateAI

Benign

0.47

PROVEAN

Benign

-0.34

N;N;.

REVEL

Benign

0.0060

Sift

Benign

0.15

T;T;.

Sift4G

Benign

1.0

T;T;T

Polyphen

0.0010

.;B;.

Vest4

0.15

MutPred

0.27

Gain of catalytic residue at T14 (P = 0.0175);Gain of catalytic residue at T14 (P = 0.0175);Gain of catalytic residue at T14 (P = 0.0175);

MVP

0.014

MPC

0.050

ClinPred

0.066

GERP RS

0.41

PromoterAI

0.0037

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.062

gMVP

0.17

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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over