rs150351852

chr7-107548327-G-A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_Strong BS1_Supporting

The NM_006348.5(COG5):c.298C>T(p.Leu100Phe) variant causes a missense change. The variant allele was found at a frequency of 0.000858 in 1,613,628 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00093 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00085 (1 hom.)
• Consequence: COG5 NM_006348.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:1
• Conservation: PhyloP100: 7.17

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 Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.06370422).
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000926 (141/152286) while in subpopulation AMR AF= 0.00451 (69/15288). AF 95% confidence interval is 0.00366. There are 1 homozygotes in gnomad4. There are 76 alleles in male gnomad4 subpopulation. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COG5	NM_006348.5	c.298C>T	p.Leu100Phe	missense_variant	4/22	ENST00000297135.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COG5	ENST00000297135.9	c.298C>T	p.Leu100Phe	missense_variant	4/22	1	NM_006348.5	P2

Frequencies

GnomAD3 genomes AF: 0.000927 AC: 141 AN: 152168 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00452

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000955

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000843 AC: 212 AN: 251422 Hom.: 1 AF XY: 0.000854 AC XY: 116 AN XY: 135880

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00217

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00116

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000851 AC: 1244 AN: 1461342 Hom.: 1 Cov.: 31 AF XY: 0.000845 AC XY: 614 AN XY: 727018

Gnomad4 AFR exome AF: 0.000329

Gnomad4 AMR exome AF: 0.00181

Gnomad4 ASJ exome AF: 0.000115

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000990

Gnomad4 OTH exome AF: 0.000729

GnomAD4 genome AF: 0.000926 AC: 141 AN: 152286 Hom.: 1 Cov.: 32 AF XY: 0.00102 AC XY: 76 AN XY: 74472

Gnomad4 AFR AF: 0.000144

Gnomad4 AMR AF: 0.00451

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000955

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00101 Hom.: 0

Bravo AF: 0.000982

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000814 AC: 7

ExAC AF: 0.000692 AC: 84

EpiCase AF: 0.00104

EpiControl AF: 0.00202

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

COG5-congenital disorder of glycosylation Uncertain:4 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jul 11, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Uncertain significance, no assertion criteria provided	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Nov 16, 2020	The heterozygous p.Leu131Phe (p.Leu100Phe) variant in COG5 was identified by our study in the compound heterozygous state, along with a likely benign variant, in 1 individual with congenital disorder of glycosylation, type IIi (commonly referred to as COG5-CDG or CDG2I). The variant has not been previously reported in individuals with COG5-CDG and has been identified in 0.21% (76/35438) of Latino chromosomes and 1 homozygote by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs150351852). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. The p.Leu131Phe variant is located in a region of COG5 that is essential to protein folding and stability, suggesting that this variant is in a functional domain and slightly supports pathogenicity (PMID: 25331899). In summary, the clinical significance of the variant is uncertain. ACMG/AMP Criteria applied: BS1, PM1 (Richards 2015). -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 17, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Nov 19, 2019

In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.81
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Uncertain	0.030
Cadd	Pathogenic	30
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.19	T;.;.;.
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D;D;D;.
M_CAP	Benign	0.025	T
MetaRNN	Benign	0.064	T;T;T;T
MetaSVM	Benign	-0.59	T
MutationAssessor	Uncertain	2.9	M;M;M;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-3.3	D;D;D;.
REVEL	Uncertain	0.37
Sift	Pathogenic	0.0	D;D;D;.
Sift4G	Pathogenic	0.0	D;D;D;.
Polyphen		1.0	D;D;.;.
Vest4		0.81
MVP		0.72
MPC		0.37
ClinPred		0.16	T
GERP RS		5.4
Varity_R		0.77
gMVP		0.64

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs150351852; hg19: chr7-107188772;