1-230659609-A-G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS1

The NM_007357.3(COG2):c.218A>G(p.Asn73Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000379 in 1,613,218 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00063 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00035 (1 hom.)
• Consequence: COG2 NM_007357.3 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 6.60

Genes affected

COG2 (HGNC:6546): (component of oligomeric golgi complex 2) This gene encodes a subunit of the conserved oligomeric Golgi complex that is required for maintaining normal structure and activity of the Golgi complex. The encoded protein specifically interacts with the USO1 vesicle docking protein and may be necessary for normal Golgi ribbon formation and trafficking of Golgi enzymes. Mutations of this gene are associated with abnormal glycosylation within the Golgi apparatus. Alternative splicing results in multiple transcript variants.[provided by RefSeq, Feb 2009]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.027139068).
• BP6: Variant 1-230659609-A-G is Benign according to our data. Variant chr1-230659609-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 718942.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00063 (96/152314) while in subpopulation AMR AF= 0.00157 (24/15302). AF 95% confidence interval is 0.00108. There are 1 homozygotes in gnomad4. There are 36 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COG2	NM_007357.3	c.218A>G	p.Asn73Ser	missense_variant	2/18	ENST00000366669.9
COG2	NM_001145036.2	c.218A>G	p.Asn73Ser	missense_variant	2/18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COG2	ENST00000366669.9	c.218A>G	p.Asn73Ser	missense_variant	2/18	1	NM_007357.3	P4

Frequencies

GnomAD3 genomes AF: 0.000631 AC: 96 AN: 152196 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000675

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00157

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.000441

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.000652 AC: 163 AN: 250080 Hom.: 1 AF XY: 0.000548 AC XY: 74 AN XY: 135064

Gnomad AFR exome AF: 0.000985

Gnomad AMR exome AF: 0.00221

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000399

Gnomad FIN exome AF: 0.0000464

Gnomad NFE exome AF: 0.000388

Gnomad OTH exome AF: 0.00230

GnomAD4 exome AF: 0.000353 AC: 516 AN: 1460904 Hom.: 1 Cov.: 31 AF XY: 0.000318 AC XY: 231 AN XY: 726612

Gnomad4 AFR exome AF: 0.000747

Gnomad4 AMR exome AF: 0.00226

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000151

Gnomad4 SAS exome AF: 0.000268

Gnomad4 FIN exome AF: 0.0000375

Gnomad4 NFE exome AF: 0.000278

Gnomad4 OTH exome AF: 0.000729

GnomAD4 genome AF: 0.000630 AC: 96 AN: 152314 Hom.: 1 Cov.: 33 AF XY: 0.000483 AC XY: 36 AN XY: 74474

Gnomad4 AFR AF: 0.000673

Gnomad4 AMR AF: 0.00157

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.000441

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.000343 Hom.: 0

Bravo AF: 0.000861

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000766 AC: 93

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.000382

EpiControl AF: 0.000356

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Congenital disorder of glycosylation, type IIq Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 24, 2024

- -

COG2-related disorder Benign:1

Likely benign, criteria provided, single submitter

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	0.12
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.47
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.53	D;.;T
Eigen	Uncertain	0.24
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.96	D;D;D
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.027	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L;L;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-3.9	D;D;D
REVEL	Benign	0.23
Sift	Pathogenic	0.0	D;D;T
Sift4G	Benign	0.087	T;T;T
Polyphen		0.45	B;.;.
Vest4		0.50
MVP		0.20
MPC		0.52
ClinPred		0.039	T
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.67
gMVP		0.38

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs201791868; hg19: chr1-230795355;