chr13-39727482-G-T

Variant names:

• chr13-39727482-G-T
• rs191156299
• NM_020751.3:c.1760G>T

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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.70
• Publications: 0 publications found

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

ACMG classification

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	c.1760G>T	p.Arg587Leu	missense_variant	Exon 18 of 19	ENST00000455146.8	NP_065802.1
COG6	NM_001145079.2	c.1760G>T	p.Arg587Leu	missense_variant	Exon 18 of 19		NP_001138551.1
COG6	XM_011535168.2	c.1760G>T	p.Arg587Leu	missense_variant	Exon 18 of 20		XP_011533470.1
COG6	NR_026745.1	n.1925G>T		non_coding_transcript_exon_variant	Exon 19 of 20

Ensembl

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

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460206 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 726566

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

African (AFR) AF: 0.00 AC: 0 AN: 33430

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26104

East Asian (EAS) AF: 0.00 AC: 0 AN: 39582

South Asian (SAS) AF: 0.00 AC: 0 AN: 86224

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5754

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1110672

Other (OTH) AF: 0.00 AC: 0 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.

GnomAD4 genome Cov.: 32

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	D
BayesDel_noAF	Uncertain	0.11
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0080	.;T
Eigen	Benign	0.065
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.87	D;D
M_CAP	Benign	0.017	T
MetaRNN	Uncertain	0.63	D;D
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.5	L;L
PhyloP100		5.7
PrimateAI	Uncertain	0.56	T
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	D
GERP RS		5.9
Varity_R		0.18
gMVP		0.63
Mutation Taster		=22/78	disease causing

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

Other links and lift over

dbSNP: rs191156299; hg19: chr13-40301619;