rs74443110

chr7-107298198-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_006348.5(COG5):c.1257A>G(p.Leu419=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00324 in 1,613,526 control chromosomes in the GnomAD database, including 100 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.014 (58 hom., cov: 32)
  • Exomes 𝑓: 0.0021 (42 hom.)
• Consequence: COG5 NM_006348.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.860

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 Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 7-107298198-T-C is Benign according to our data. Variant chr7-107298198-T-C is described in ClinVar as [Benign]. Clinvar id is 358462.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.86 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0143 (2185/152284) while in subpopulation AFR AF= 0.0478 (1986/41554). AF 95% confidence interval is 0.046. There are 58 homozygotes in gnomad4. There are 1007 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 57 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COG5	NM_006348.5	c.1257A>G	p.Leu419=	synonymous_variant	12/22	ENST00000297135.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COG5	ENST00000297135.9	c.1257A>G	p.Leu419=	synonymous_variant	12/22	1	NM_006348.5	P2
COG5	ENST00000347053.8	c.1257A>G	p.Leu419=	synonymous_variant	12/21	1		A2
COG5	ENST00000393603.7	c.1257A>G	p.Leu419=	synonymous_variant	12/21	1

Frequencies

GnomAD3 genomes AF: 0.0143 AC: 2175 AN: 152166 Hom.: 57 Cov.: 32

Gnomad AFR AF: 0.0477

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00536

Gnomad ASJ AF: 0.0184

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000500

Gnomad OTH AF: 0.00766

GnomAD3 exomes AF: 0.00451 AC: 1133 AN: 251284 Hom.: 21 AF XY: 0.00368 AC XY: 500 AN XY: 135822

Gnomad AFR exome AF: 0.0474

Gnomad AMR exome AF: 0.00301

Gnomad ASJ exome AF: 0.0151

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000713

Gnomad OTH exome AF: 0.00392

GnomAD4 exome AF: 0.00208 AC: 3046 AN: 1461242 Hom.: 42 Cov.: 30 AF XY: 0.00197 AC XY: 1430 AN XY: 726922

Gnomad4 AFR exome AF: 0.0508

Gnomad4 AMR exome AF: 0.00356

Gnomad4 ASJ exome AF: 0.0157

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000162

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000349

Gnomad4 OTH exome AF: 0.00552

GnomAD4 genome AF: 0.0143 AC: 2185 AN: 152284 Hom.: 58 Cov.: 32 AF XY: 0.0135 AC XY: 1007 AN XY: 74472

Gnomad4 AFR AF: 0.0478

Gnomad4 AMR AF: 0.00536

Gnomad4 ASJ AF: 0.0184

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000500

Gnomad4 OTH AF: 0.00758

Alfa AF: 0.00750 Hom.: 10

Bravo AF: 0.0165

Asia WGS AF: 0.00231 AC: 8 AN: 3476

EpiCase AF: 0.00104

EpiControl AF: 0.00113

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

COG5-congenital disorder of glycosylation Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 01, 2016

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

COG5-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 23, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
Cadd	Benign	1.4
Dann	Benign	0.61
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs74443110; hg19: chr7-106938643;