NM_006348.5:c.1756C>T

Variant names:

• chr7-107248493-G-A
• rs151129529
• NM_006348.5:c.1756C>T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BS1_Supporting

The NM_006348.5(COG5):​c.1756C>T​(p.His586Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.000184 in 1,562,248 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00076 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00012 (1 hom.)
• Consequence: COG5 NM_006348.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4 B:1
• Conservation: PhyloP100: 5.81

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 -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.011014938).
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000759 (111/146234) while in subpopulation AFR AF= 0.00263 (104/39520). AF 95% confidence interval is 0.00222. There are 0 homozygotes in gnomad4. There are 39 alleles in male gnomad4 subpopulation. Median coverage is 31. 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 rank	MANE	Protein	UniProt
COG5	NM_006348.5	c.1756C>T	p.His586Tyr	missense_variant	Exon 17 of 22	ENST00000297135.9	NP_006339.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COG5	ENST00000297135.9	c.1756C>T	p.His586Tyr	missense_variant	Exon 17 of 22	1	NM_006348.5	ENSP00000297135.4

Frequencies

GnomAD3 genomes AF: 0.000753 AC: 110 AN: 146118 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00261

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000342

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000150

Gnomad OTH AF: 0.000494

GnomAD3 exomes AF: 0.000238 AC: 58 AN: 243846 Hom.: 0 AF XY: 0.000197 AC XY: 26 AN XY: 132184

Gnomad AFR exome AF: 0.00215

Gnomad AMR exome AF: 0.000267

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000135

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000807

Gnomad OTH exome AF: 0.000337

GnomAD4 exome AF: 0.000124 AC: 176 AN: 1416014 Hom.: 1 Cov.: 27 AF XY: 0.000123 AC XY: 87 AN XY: 706418

Gnomad4 AFR exome AF: 0.00239

Gnomad4 AMR exome AF: 0.000274

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000119

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000390

Gnomad4 OTH exome AF: 0.000442

GnomAD4 genome AF: 0.000759 AC: 111 AN: 146234 Hom.: 0 Cov.: 31 AF XY: 0.000550 AC XY: 39 AN XY: 70872

Gnomad4 AFR AF: 0.00263

Gnomad4 AMR AF: 0.000342

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000150

Gnomad4 OTH AF: 0.000488

Alfa AF: 0.000114 Hom.: 0

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000280 AC: 34

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4 Benign:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

COG5-congenital disorder of glycosylation Uncertain:2

Mar 28, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 617 of the COG5 protein (p.His617Tyr). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with COG5-related conditions. ClinVar contains an entry for this variant (Variation ID: 487322). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not specified Uncertain:1

Sep 26, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: COG5 c.1756C>T (p.His586Tyr) results in a conservative amino acid change in the encoded protein sequence. Three of three in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00024 in 243846 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in COG5 causing Congenital Disorder Of Glycosylation, Type 2i, allowing no conclusion about variant significance. To our knowledge, no occurrence of c.1756C>T in individuals affected with Congenital Disorder Of Glycosylation, Type 2i and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 487322). Based on the evidence outlined above, the variant was classified as uncertain significance. -

not provided Uncertain:1

Feb 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

COG5: PM2:Supporting, BP4 -

COG5-related disorder Benign:1

Nov 27, 2023

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	16
DANN	Benign	0.86
DEOGEN2	Benign	0.0034	T;.;.
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.39
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.64	T;T;T
M_CAP	Benign	0.0095	T
MetaRNN	Benign	0.011	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L;.;.
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-0.93	N;N;N
REVEL	Benign	0.089
Sift	Benign	0.14	T;T;T
Sift4G	Uncertain	0.034	D;T;T
Polyphen		0.0030	B;B;.
Vest4		0.43
MVP		0.55
MPC		0.061
ClinPred		0.012	T
GERP RS		4.0
Varity_R		0.053
gMVP		0.32

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: rs151129529; hg19: chr7-106888938;