rs143773937

Positions:

• chr7-107324511-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_006348.5(COG5):​c.1037C>T​(p.Pro346Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000566 in 1,602,608 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00063 (2 hom., cov: 33)
  • Exomes 𝑓: 0.00056 (1 hom.)
• Consequence: COG5 NM_006348.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:3
• Conservation: PhyloP100: 5.24

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005508989).
• BP6: Variant 7-107324511-G-A is Benign according to our data. Variant chr7-107324511-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 286064.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2, Benign=1}. Variant chr7-107324511-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.000559 (811/1450536) while in subpopulation MID AF= 0.00175 (10/5720). AF 95% confidence interval is 0.000948. There are 1 homozygotes in gnomad4_exome. There are 424 alleles in male gnomad4_exome subpopulation. Median coverage is 28. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COG5	NM_006348.5	c.1037C>T	p.Pro346Leu	missense_variant	11/22	ENST00000297135.9	NP_006339.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COG5	ENST00000297135.9	c.1037C>T	p.Pro346Leu	missense_variant	11/22	1	NM_006348.5	ENSP00000297135.4
COG5	ENST00000347053.8	c.1037C>T	p.Pro346Leu	missense_variant	11/21	1		ENSP00000334703.3
COG5	ENST00000393603.7	c.1037C>T	p.Pro346Leu	missense_variant	11/21	1		ENSP00000377228.3

Frequencies

GnomAD3 genomes AF: 0.000632 AC: 96 AN: 151954 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.000580

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.0101

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000412

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000890 AC: 222 AN: 249428 Hom.: 0 AF XY: 0.000926 AC XY: 125 AN XY: 134932

Gnomad AFR exome AF: 0.000808

Gnomad AMR exome AF: 0.000848

Gnomad ASJ exome AF: 0.0103

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000133

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000549

Gnomad OTH exome AF: 0.00181

GnomAD4 exome AF: 0.000559 AC: 811 AN: 1450536 Hom.: 1 Cov.: 28 AF XY: 0.000588 AC XY: 424 AN XY: 721216

Gnomad4 AFR exome AF: 0.000390

Gnomad4 AMR exome AF: 0.000743

Gnomad4 ASJ exome AF: 0.0113

Gnomad4 EAS exome AF: 0.0000762

Gnomad4 SAS exome AF: 0.000156

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000327

Gnomad4 OTH exome AF: 0.00139

GnomAD4 genome AF: 0.000631 AC: 96 AN: 152072 Hom.: 2 Cov.: 33 AF XY: 0.000605 AC XY: 45 AN XY: 74320

Gnomad4 AFR AF: 0.000578

Gnomad4 AMR AF: 0.000458

Gnomad4 ASJ AF: 0.0101

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000412

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.00133 Hom.: 0

Bravo AF: 0.000816

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.000932 AC: 8

ExAC AF: 0.000873 AC: 106

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

COG5-congenital disorder of glycosylation Uncertain:1 Benign:1

Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 21, 2024	- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Jan 26, 2016

- -

COG5-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 04, 2020

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

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 02, 2022

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.11	T;.;.
Eigen	Benign	0.13
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.91	D;D;D
M_CAP	Benign	0.025	D
MetaRNN	Benign	0.0055	T;T;T
MetaSVM	Benign	-0.84	T
MutationAssessor	Uncertain	2.2	M;M;M
PrimateAI	Benign	0.29	T
PROVEAN	Uncertain	-3.7	D;D;D
REVEL	Benign	0.087
Sift	Uncertain	0.029	D;D;D
Sift4G	Benign	0.061	T;T;T
Polyphen		0.10	B;B;.
Vest4		0.20
MVP		0.57
MPC		0.064
ClinPred		0.043	T
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.23
gMVP		0.28

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: rs143773937; hg19: chr7-106964956;