rs41276187

Positions:

• chr7-107298208-T-C
• chr7-107298208-T-G

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.1247A>G​(p.Tyr416Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0062 in 1,613,714 control chromosomes in the GnomAD database, including 43 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 0.0052 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0063 (39 hom.)
• Consequence: COG5 NM_006348.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: -0.583

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=0.003083676).
• BP6: Variant 7-107298208-T-C is Benign according to our data. Variant chr7-107298208-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 194075.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Benign=3, Uncertain_significance=1}. Variant chr7-107298208-T-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00516 (786/152272) while in subpopulation NFE AF= 0.00798 (543/68014). AF 95% confidence interval is 0.00743. There are 4 homozygotes in gnomad4. There are 367 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COG5	NM_006348.5	c.1247A>G	p.Tyr416Cys	missense_variant	12/22	ENST00000297135.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COG5	ENST00000297135.9	c.1247A>G	p.Tyr416Cys	missense_variant	12/22	1	NM_006348.5	P2
COG5	ENST00000347053.8	c.1247A>G	p.Tyr416Cys	missense_variant	12/21	1		A2
COG5	ENST00000393603.7	c.1247A>G	p.Tyr416Cys	missense_variant	12/21	1

Frequencies

GnomAD3 genomes AF: 0.00517 AC: 786 AN: 152154 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00138

Gnomad AMI AF: 0.0713

Gnomad AMR AF: 0.00471

Gnomad ASJ AF: 0.00576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00113

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00798

Gnomad OTH AF: 0.00574

GnomAD3 exomes AF: 0.00474 AC: 1192 AN: 251284 Hom.: 4 AF XY: 0.00478 AC XY: 649 AN XY: 135824

Gnomad AFR exome AF: 0.00111

Gnomad AMR exome AF: 0.00515

Gnomad ASJ exome AF: 0.00506

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.000490

Gnomad FIN exome AF: 0.00106

Gnomad NFE exome AF: 0.00767

Gnomad OTH exome AF: 0.00572

GnomAD4 exome AF: 0.00631 AC: 9222 AN: 1461442 Hom.: 39 Cov.: 30 AF XY: 0.00620 AC XY: 4509 AN XY: 727048

Gnomad4 AFR exome AF: 0.00105

Gnomad4 AMR exome AF: 0.00521

Gnomad4 ASJ exome AF: 0.00455

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000499

Gnomad4 FIN exome AF: 0.00152

Gnomad4 NFE exome AF: 0.00749

Gnomad4 OTH exome AF: 0.00566

GnomAD4 genome AF: 0.00516 AC: 786 AN: 152272 Hom.: 4 Cov.: 32 AF XY: 0.00493 AC XY: 367 AN XY: 74470

Gnomad4 AFR AF: 0.00137

Gnomad4 AMR AF: 0.00471

Gnomad4 ASJ AF: 0.00576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.00113

Gnomad4 NFE AF: 0.00798

Gnomad4 OTH AF: 0.00568

Alfa AF: 0.00670 Hom.: 5

Bravo AF: 0.00506

TwinsUK AF: 0.00431 AC: 16

ALSPAC AF: 0.00934 AC: 36

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.00512 AC: 44

ExAC AF: 0.00458 AC: 556

Asia WGS AF: 0.000289 AC: 1 AN: 3476

EpiCase AF: 0.00884

EpiControl AF: 0.0107

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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. -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 05, 2015	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 27, 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. -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	COG5: BP4, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Apr 12, 2016	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.055
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	0.044
DANN	Benign	0.72
DEOGEN2	Benign	0.0066	T;.;.
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.68	T;T;T
MetaRNN	Benign	0.0031	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N;N;N
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.69	N;N;N
REVEL	Benign	0.046
Sift	Benign	0.14	T;T;T
Sift4G	Benign	0.18	T;T;T
Polyphen		0.0	B;B;.
Vest4		0.21
MVP		0.34
MPC		0.065
ClinPred		0.00032	T
GERP RS		-4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.052
gMVP		0.38

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: rs41276187; hg19: chr7-106938653;