rs1554464495

Positions:

• chr7-107558113-AC-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The ENST00000297135.9(COG5):​c.96del​(p.Cys33ValfsTer6) variant causes a frameshift, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,358 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: COG5 ENST00000297135.9 frameshift, splice_region
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: -0.113

Genes affected

COG5 (HGNC:14857): (component of oligomeric golgi complex 5) The protein encoded by this gene is one of eight proteins (Cog1-8) which form a Golgi-localized complex (COG) required for normal Golgi morphology and function. The encoded protein is organized with conserved oligomeric Golgi complex components 6, 7 and 8 into a sub-complex referred to as lobe B. Alternative splicing results in multiple transcript variants. Mutations in this gene result in congenital disorder of glycosylation type 2I.[provided by RefSeq, Jan 2011]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 33 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 7-107558113-AC-A is Pathogenic according to our data. Variant chr7-107558113-AC-A is described in ClinVar as [Pathogenic]. Clinvar id is 523949.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COG5	NM_006348.5	c.96del	p.Cys33ValfsTer6	frameshift_variant, splice_region_variant	2/22	ENST00000297135.9	NP_006339.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COG5	ENST00000297135.9	c.96del	p.Cys33ValfsTer6	frameshift_variant, splice_region_variant	2/22	1	NM_006348.5	ENSP00000297135	P2
COG5	ENST00000347053.8	c.96del	p.Cys33ValfsTer6	frameshift_variant, splice_region_variant	2/21	1		ENSP00000334703	A2
COG5	ENST00000393603.7	c.96del	p.Cys33ValfsTer6	frameshift_variant, splice_region_variant	2/21	1		ENSP00000377228
COG5	ENST00000605888.1	c.96del	p.Cys33ValfsTer6	frameshift_variant, splice_region_variant	2/6	2		ENSP00000476238

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461358 Hom.: 0 Cov.: 33 AF XY: 0.00000275 AC XY: 2 AN XY: 726994

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

COG5-congenital disorder of glycosylation Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Apr 29, 2023	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 523949). This premature translational stop signal has been observed in individual(s) with COG5-congenital disorder of glycosylation (PMID: 23228021). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Cys64Valfs*6) in the COG5 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in COG5 are known to be pathogenic (PMID: 23228021). -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 09, 2020	- -

COG5-related disorder Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 11, 2024

The COG5 c.189delG variant is predicted to result in a frameshift and premature protein termination (p.Cys64Valfs*6). This variant has been reported in the compound heterozygous state in a patient with a congenital disorder of glycosylation (Patient 3, Rymen et al. 2012. PubMed ID: 2322802). To our knowledge, this variant has not been reported in the in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Frameshift variants in COG5 are expected to be pathogenic. This variant is interpreted as likely pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Mar 28, 2019

Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 23228021) -

Computational scores

Source: dbNSFP v4.3

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

LitVar

Other links and lift over

dbSNP: rs1554464495; hg19: chr7-107198558;