rs730882236

Variant names:

• chr13-39699477-A-G
• rs730882236
• NM_020751.3:c.1167-24A>G

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PS3 PM2 PP3 PP5_Very_Strong

The NM_020751.3(COG6):​c.1167-24A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000002 in 1,000,220 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV004710980: Functional studies showed this variant largely replaces the canonical acceptor site, resulting in pronounced reduction of the normal transcript and consequive deficiency of COG6 protein (Shaheen et al. 2013. PubMed ID: 23606727).".

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000020 (0 hom.)
• Consequence: COG6 NM_020751.3 intron
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12
• Conservation: PhyloP100: 0.0340
• Publications: 12 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: 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

ACMG classification

Our verdict: Pathogenic. The variant received 15 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV004710980: Functional studies showed this variant largely replaces the canonical acceptor site, resulting in pronounced reduction of the normal transcript and consequive deficiency of COG6 protein (Shaheen et al. 2013. PubMed ID: 23606727).
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 13-39699477-A-G is Pathogenic according to our data. Variant chr13-39699477-A-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 183333.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COG6	NM_020751.3	MANE Select	c.1167-24A>G		intron	N/A	NP_065802.1	Q9Y2V7-1
	COG6	NM_001145079.2		c.1167-24A>G		intron	N/A	NP_001138551.1	A0A140VJG7
	COG6	NR_026745.1		n.1332-24A>G		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COG6	ENST00000455146.8	TSL:1 MANE Select	c.1167-24A>G		intron	N/A	ENSP00000397441.2	Q9Y2V7-1
	COG6	ENST00000416691.6	TSL:1	c.1167-24A>G		intron	N/A	ENSP00000403733.1	Q9Y2V7-2
	COG6	ENST00000356576.8	TSL:1	n.*1004-24A>G		intron	N/A	ENSP00000348983.4	Q9Y2V7-4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000200 AC: 2 AN: 1000220 Hom.: 0 Cov.: 13 AF XY: 0.00 AC XY: 0 AN XY: 518504

⚠️ 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: 24602

American (AMR) AF: 0.00 AC: 0 AN: 43870

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23174

East Asian (EAS) AF: 0.00 AC: 0 AN: 37406

South Asian (SAS) AF: 0.00 AC: 0 AN: 76762

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53016

Middle Eastern (MID) AF: 0.000426 AC: 2 AN: 4690

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 691934

Other (OTH) AF: 0.00 AC: 0 AN: 44766

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000587 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
4	-	-	COG6-congenital disorder of glycosylation (4)
3	-	-	not provided (3)
2	-	-	COG6-related disorder (2)
2	-	-	Hypohidrosis-enamel hypoplasia-palmoplantar keratoderma-intellectual disability syndrome (2)
1	-	-	Hypohidrosis;C3714756:Intellectual disability (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	11
DANN	Benign	0.87
PhyloP100		0.034
Mutation Taster		=22/78	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.51		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.51		Position offset: -13
DS_AL_spliceai		0.25		Position offset: 24

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs730882236; hg19: chr13-40273614;