Genetic Variant NM_020751.3:c.1760G>T (chr13-39727482-G-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_020751.3(COG6):c.1760G>T(p.Arg587Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,460,206 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R587C) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

COG6
NM_020751.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.70

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: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COG6	NM_020751.3 link	c.1760G>T	p.Arg587Leu	missense_variant	Exon 18 of 19	ENST00000455146.8	NP_065802.1	Q9Y2V7-1A0A024RDW5
COG6	NM_001145079.2 link	c.1760G>T	p.Arg587Leu	missense_variant	Exon 18 of 19		NP_001138551.1	Q9Y2V7-2A0A140VJG7
COG6	XM_011535168.2 link	c.1760G>T	p.Arg587Leu	missense_variant	Exon 18 of 20		XP_011533470.1
COG6	NR_026745.1 link	n.1925G>T		non_coding_transcript_exon_variant	Exon 19 of 20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
COG6	ENST00000455146.8 link	c.1760G>T	p.Arg587Leu	missense_variant	Exon 18 of 19	1	NM_020751.3	ENSP00000397441.2	Q9Y2V7-1
COG6	ENST00000416691.6 link	c.1760G>T	p.Arg587Leu	missense_variant	Exon 18 of 19	1		ENSP00000403733.1	Q9Y2V7-2
COG6	ENST00000356576.8 link	n.*1597G>T		non_coding_transcript_exon_variant	Exon 19 of 20	1		ENSP00000348983.4	Q9Y2V7-4
COG6	ENST00000356576.8 link	n.*1597G>T		3_prime_UTR_variant	Exon 19 of 20	1		ENSP00000348983.4	Q9Y2V7-4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1460206

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726566

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33430

American (AMR)

AF:

0.00

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26104

East Asian (EAS)

AF:

0.00

AC:

AN:

39582

South Asian (SAS)

AF:

0.00

AC:

AN:

86224

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53412

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5754

European-Non Finnish (NFE)

AF:

9.00e-7

AC:

AN:

1110672

Other (OTH)

AF:

0.00

AC:

AN:

60308

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.275

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

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Pathogenic

0.25

BayesDel_noAF

Uncertain

0.11

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0080

.;T

Eigen

Benign

0.065

Eigen_PC

Uncertain

0.28

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.87

D;D

M_CAP

Benign

0.017

MetaRNN

Uncertain

0.63

D;D

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.5

L;L

PhyloP100

5.7

PrimateAI

Uncertain

0.56

PROVEAN

Uncertain

-2.4

N;N

REVEL

Uncertain

0.32

Sift

Benign

0.17

T;T

Sift4G

Benign

0.21

T;T

Polyphen

0.0

.;B

Vest4

0.83

MutPred

0.50

Gain of catalytic residue at F585 (P = 0.0107);Gain of catalytic residue at F585 (P = 0.0107);

MVP

0.52

MPC

0.064

ClinPred

0.95

GERP RS

5.9

Varity_R

0.18

gMVP

0.63

Mutation Taster

=22/78

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over