17-73193127-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_018714.3(COG1):c.58G>C(p.Ala20Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00479 in 1,576,020 control chromosomes in the GnomAD database, including 71 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.010 (16 hom., cov: 31)
  • Exomes 𝑓: 0.0042 (55 hom.)
• Consequence: COG1 NM_018714.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 5.65

Genes affected

COG1 (HGNC:6545): (component of oligomeric golgi complex 1) 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. It is thought that this protein is required for steps in the normal medial and trans Golgi-associated processing of glycoconjugates and plays a role in the organization of the Golgi-localized complex. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0084144175).
• BP6: Variant 17-73193127-G-C is Benign according to our data. Variant chr17-73193127-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 324955.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-73193127-G-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0105 (1593/151948) while in subpopulation NFE AF= 0.0169 (1149/67822). AF 95% confidence interval is 0.0161. There are 16 homozygotes in gnomad4. There are 720 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 16 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COG1	NM_018714.3	c.58G>C	p.Ala20Pro	missense_variant	1/14	ENST00000299886.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COG1	ENST00000299886.9	c.58G>C	p.Ala20Pro	missense_variant	1/14	1	NM_018714.3	P1
COG1	ENST00000438720.7	c.58G>C	p.Ala20Pro	missense_variant	1/13	1
COG1	ENST00000582587.2	c.37G>C	p.Ala13Pro	missense_variant, NMD_transcript_variant	1/3	3

Frequencies

GnomAD3 genomes AF: 0.0105 AC: 1592 AN: 151834 Hom.: 16 Cov.: 31

Gnomad AFR AF: 0.00343

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00858

Gnomad ASJ AF: 0.00663

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00415

Gnomad FIN AF: 0.00946

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0169

Gnomad OTH AF: 0.0125

GnomAD3 exomes AF: 0.0112 AC: 2678 AN: 240096 Hom.: 23 AF XY: 0.0117 AC XY: 1538 AN XY: 131446

Gnomad AFR exome AF: 0.00336

Gnomad AMR exome AF: 0.00558

Gnomad ASJ exome AF: 0.00624

Gnomad EAS exome AF: 0.0000563

Gnomad SAS exome AF: 0.00561

Gnomad FIN exome AF: 0.0127

Gnomad NFE exome AF: 0.0177

Gnomad OTH exome AF: 0.00855

GnomAD4 exome AF: 0.00418 AC: 5949 AN: 1424072 Hom.: 55 Cov.: 35 AF XY: 0.00438 AC XY: 3106 AN XY: 709422

Gnomad4 AFR exome AF: 0.000990

Gnomad4 AMR exome AF: 0.00363

Gnomad4 ASJ exome AF: 0.00286

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00371

Gnomad4 FIN exome AF: 0.00820

Gnomad4 NFE exome AF: 0.00434

Gnomad4 OTH exome AF: 0.00415

GnomAD4 genome AF: 0.0105 AC: 1593 AN: 151948 Hom.: 16 Cov.: 31 AF XY: 0.00970 AC XY: 720 AN XY: 74260

Gnomad4 AFR AF: 0.00342

Gnomad4 AMR AF: 0.00857

Gnomad4 ASJ AF: 0.00663

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00436

Gnomad4 FIN AF: 0.00946

Gnomad4 NFE AF: 0.0169

Gnomad4 OTH AF: 0.0123

Alfa AF: 0.0133 Hom.: 10

Bravo AF: 0.0108

ESP6500AA AF: 0.00410 AC: 18

ESP6500EA AF: 0.0179 AC: 154

ExAC AF: 0.0114 AC: 1375

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

COG1 congenital disorder of glycosylation Benign:2

Likely benign, 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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Oct 30, 2023

See Variant Classification Assertion Criteria. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.77
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.34
Cadd	Pathogenic	32
Dann	Benign	0.95
DEOGEN2	Benign	0.028	T;T
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Benign	0.65	D
LIST_S2	Uncertain	0.90	D;D
MetaRNN	Benign	0.0084	T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.90	D
Sift4G	Benign	0.27	T;T
Polyphen		0.99	.;D
Vest4		0.18
MPC		2.0
ClinPred		0.025	T
GERP RS		3.6
Varity_R		0.79

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: rs142719529; hg19: chr17-71189266;