rs387906959

Variant names:

• chr13-39723394-G-C
• rs387906959
• NM_020751.3:c.1646G>C

Your query was ambiguous. Multiple possible variants found:

• chr13-39723394-G-C
• chr13-39723394-G-T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PM5 PP3_Moderate

The NM_020751.3(COG6):​c.1646G>C​(p.Gly549Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,459,106 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G549C) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: COG6 NM_020751.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.50
• Publications: 17 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr13-39723394-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 30628.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.89

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COG6	NM_020751.3	c.1646G>C	p.Gly549Ala	missense_variant	Exon 16 of 19	ENST00000455146.8	NP_065802.1
COG6	NM_001145079.2	c.1646G>C	p.Gly549Ala	missense_variant	Exon 16 of 19		NP_001138551.1
COG6	XM_011535168.2	c.1646G>C	p.Gly549Ala	missense_variant	Exon 16 of 20		XP_011533470.1
COG6	NR_026745.1	n.1811G>C		non_coding_transcript_exon_variant	Exon 17 of 20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COG6	ENST00000455146.8	c.1646G>C	p.Gly549Ala	missense_variant	Exon 16 of 19	1	NM_020751.3	ENSP00000397441.2
COG6	ENST00000416691.6	c.1646G>C	p.Gly549Ala	missense_variant	Exon 16 of 19	1		ENSP00000403733.1
COG6	ENST00000356576.8	n.*1483G>C		non_coding_transcript_exon_variant	Exon 17 of 20	1		ENSP00000348983.4
COG6	ENST00000356576.8	n.*1483G>C		3_prime_UTR_variant	Exon 17 of 20	1		ENSP00000348983.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000399 AC: 1 AN: 250770 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1459106 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 726014

African (AFR) AF: 0.00 AC: 0 AN: 33398

American (AMR) AF: 0.00 AC: 0 AN: 44632

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26088

East Asian (EAS) AF: 0.00 AC: 0 AN: 39642

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86196

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53342

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1109770

Other (OTH) AF: 0.00 AC: 0 AN: 60284

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Uncertain	0.089	D
BayesDel_noAF	Uncertain	-0.010
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.20	.;T
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.91	D;D
M_CAP	Benign	0.044	D
MetaRNN	Pathogenic	0.89	D;D
MetaSVM	Uncertain	-0.25	T
MutationAssessor	Uncertain	2.2	M;M
PhyloP100		7.5
PrimateAI	Uncertain	0.69	T
PROVEAN	Pathogenic	-4.4	D;D
REVEL	Uncertain	0.60
Sift	Uncertain	0.0060	D;D
Sift4G	Uncertain	0.054	T;T
Polyphen		0.78	.;P
Vest4		0.70
MutPred		0.78		Gain of catalytic residue at Y552 (P = 0.0073);Gain of catalytic residue at Y552 (P = 0.0073);
MVP		0.81
MPC		0.17
ClinPred		0.95	D
GERP RS		5.7
Varity_R		0.50
gMVP		0.75
Mutation Taster		=48/52	disease causing

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

Other links and lift over

dbSNP: rs387906959; hg19: chr13-40297531;