rs35393416

Positions:

• chr7-107298193-T-C

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.1262A>G​(p.His421Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00383 in 1,613,208 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 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 0.0028 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0039 (21 hom.)
• Consequence: COG5 NM_006348.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 1.86

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=0.0037671328).
• BP6: Variant 7-107298193-T-C is Benign according to our data. Variant chr7-107298193-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 358461.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1, Benign=1}. Variant chr7-107298193-T-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00281 (428/152302) while in subpopulation NFE AF= 0.00463 (315/68006). AF 95% confidence interval is 0.00421. There are 0 homozygotes in gnomad4. There are 196 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 21 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COG5	NM_006348.5	c.1262A>G	p.His421Arg	missense_variant	12/22	ENST00000297135.9	NP_006339.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COG5	ENST00000297135.9	c.1262A>G	p.His421Arg	missense_variant	12/22	1	NM_006348.5	ENSP00000297135.4
COG5	ENST00000347053.8	c.1262A>G	p.His421Arg	missense_variant	12/21	1		ENSP00000334703.3
COG5	ENST00000393603.7	c.1262A>G	p.His421Arg	missense_variant	12/21	1		ENSP00000377228.3

Frequencies

GnomAD3 genomes AF: 0.00281 AC: 427 AN: 152184 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000579

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00268

Gnomad ASJ AF: 0.00374

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00414

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00462

Gnomad OTH AF: 0.00383

GnomAD3 exomes AF: 0.00347 AC: 873 AN: 251248 Hom.: 7 AF XY: 0.00389 AC XY: 528 AN XY: 135806

Gnomad AFR exome AF: 0.000677

Gnomad AMR exome AF: 0.00243

Gnomad ASJ exome AF: 0.00298

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00448

Gnomad FIN exome AF: 0.000832

Gnomad NFE exome AF: 0.00492

Gnomad OTH exome AF: 0.00555

GnomAD4 exome AF: 0.00394 AC: 5758 AN: 1460906 Hom.: 21 Cov.: 30 AF XY: 0.00410 AC XY: 2978 AN XY: 726736

Gnomad4 AFR exome AF: 0.000478

Gnomad4 AMR exome AF: 0.00244

Gnomad4 ASJ exome AF: 0.00310

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00488

Gnomad4 FIN exome AF: 0.00137

Gnomad4 NFE exome AF: 0.00419

Gnomad4 OTH exome AF: 0.00484

GnomAD4 genome AF: 0.00281 AC: 428 AN: 152302 Hom.: 0 Cov.: 32 AF XY: 0.00263 AC XY: 196 AN XY: 74482

Gnomad4 AFR AF: 0.000577

Gnomad4 AMR AF: 0.00268

Gnomad4 ASJ AF: 0.00374

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00415

Gnomad4 FIN AF: 0.000377

Gnomad4 NFE AF: 0.00463

Gnomad4 OTH AF: 0.00379

Alfa AF: 0.00423 Hom.: 7

Bravo AF: 0.00296

TwinsUK AF: 0.00297 AC: 11

ALSPAC AF: 0.00467 AC: 18

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00430 AC: 37

ExAC AF: 0.00344 AC: 417

Asia WGS AF: 0.000867 AC: 3 AN: 3476

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 06, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Sep 06, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2024	COG5: BP4, BS2 -

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

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
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. -

COG5-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 20, 2022

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	0.073
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	13
DANN	Benign	0.66
DEOGEN2	Benign	0.0043	T;.;.
Eigen	Benign	-0.79
Eigen_PC	Benign	-0.70
FATHMM_MKL	Benign	0.44	N
LIST_S2	Benign	0.63	T;T;T
MetaRNN	Benign	0.0038	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.90	L;L;L
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.68	N;N;N
REVEL	Benign	0.043
Sift	Benign	0.34	T;T;T
Sift4G	Benign	0.37	T;T;T
Polyphen		0.0060	B;B;.
Vest4		0.31
MVP		0.53
MPC		0.064
ClinPred		0.0048	T
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.043
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: rs35393416; hg19: chr7-106938638; COSMIC: COSV99773705;