rs35581984

Variant names:

• chr7-107248422-G-A
• rs35581984
• NM_006348.5:c.1827C>T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_006348.5(COG5):​c.1827C>T​(p.Ile609Ile) variant causes a synonymous change. The variant allele was found at a frequency of 0.0377 in 1,610,482 control chromosomes in the GnomAD database, including 1,325 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.032 (128 hom., cov: 31)
  • Exomes 𝑓: 0.038 (1197 hom.)
• Consequence: COG5 NM_006348.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 3.61
• Publications: 4 publications found

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]

COG5 Gene-Disease associations (from GenCC):

• COG5-congenital disorder of glycosylation

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, Laboratory for Molecular Medicine, Orphanet, G2P

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.35).
• BP6: Variant 7-107248422-G-A is Benign according to our data. Variant chr7-107248422-G-A is described in ClinVar as Benign. ClinVar VariationId is 358456.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.032 (4846/151620) while in subpopulation NFE AF = 0.0465 (3160/67940). AF 95% confidence interval is 0.0452. There are 128 homozygotes in GnomAd4. There are 2321 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 128 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COG5	NM_006348.5	c.1827C>T	p.Ile609Ile	synonymous_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.1827C>T	p.Ile609Ile	synonymous_variant	Exon 17 of 22	1	NM_006348.5	ENSP00000297135.4

Frequencies

GnomAD3 genomes AF: 0.0320 AC: 4846 AN: 151504 Hom.: 128 Cov.: 31

Gnomad AFR AF: 0.00970

Gnomad AMI AF: 0.0175

Gnomad AMR AF: 0.0318

Gnomad ASJ AF: 0.0577

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00668

Gnomad FIN AF: 0.0454

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0465

Gnomad OTH AF: 0.0380

GnomAD2 exomes AF: 0.0322 AC: 8096 AN: 251292 AF XY: 0.0320

Gnomad AFR exome AF: 0.00849

Gnomad AMR exome AF: 0.0225

Gnomad ASJ exome AF: 0.0561

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.0432

Gnomad NFE exome AF: 0.0461

Gnomad OTH exome AF: 0.0364

GnomAD4 exome AF: 0.0383 AC: 55895 AN: 1458862 Hom.: 1197 Cov.: 30 AF XY: 0.0376 AC XY: 27289 AN XY: 725866

African (AFR) AF: 0.00751 AC: 251 AN: 33440

American (AMR) AF: 0.0235 AC: 1052 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.0571 AC: 1491 AN: 26114

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39670

South Asian (SAS) AF: 0.00718 AC: 619 AN: 86218

European-Finnish (FIN) AF: 0.0425 AC: 2261 AN: 53240

Middle Eastern (MID) AF: 0.0153 AC: 88 AN: 5760

European-Non Finnish (NFE) AF: 0.0433 AC: 48045 AN: 1109406

Other (OTH) AF: 0.0346 AC: 2086 AN: 60304

GnomAD4 genome AF: 0.0320 AC: 4846 AN: 151620 Hom.: 128 Cov.: 31 AF XY: 0.0313 AC XY: 2321 AN XY: 74080

African (AFR) AF: 0.00968 AC: 400 AN: 41342

American (AMR) AF: 0.0317 AC: 482 AN: 15216

Ashkenazi Jewish (ASJ) AF: 0.0577 AC: 200 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5140

South Asian (SAS) AF: 0.00690 AC: 33 AN: 4782

European-Finnish (FIN) AF: 0.0454 AC: 473 AN: 10428

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0465 AC: 3160 AN: 67940

Other (OTH) AF: 0.0376 AC: 79 AN: 2102

Alfa AF: 0.0424 Hom.: 292

Bravo AF: 0.0297

Asia WGS AF: 0.00433 AC: 16 AN: 3478

EpiCase AF: 0.0415

EpiControl AF: 0.0443

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

COG5-congenital disorder of glycosylation Benign:2

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not specified Benign:1

Jan 25, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.35
CADD	Benign	8.4
DANN	Benign	0.73
PhyloP100		3.6
Mutation Taster		=97/3	polymorphism (auto)

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

Other links and lift over

dbSNP: rs35581984; hg19: chr7-106888867; COSMIC: COSV51751114;