rs142433421

Variant names:

• chr7-107248423-A-G
• rs142433421
• NM_006348.5:c.1826T>C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_006348.5(COG5):​c.1826T>C​(p.Ile609Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000463 in 1,612,088 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. I609I) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.00077 (2 hom., cov: 31)
  • Exomes 𝑓: 0.00043 (9 hom.)
• Consequence: COG5 NM_006348.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: 8.14
• Publications: 6 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: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: PanelApp Australia, G2P, Laboratory for Molecular Medicine, ClinGen, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010679007).
• BP6: Variant 7-107248423-A-G is Benign according to our data. Variant chr7-107248423-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 225317.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00077 (117/151904) while in subpopulation EAS AF = 0.0214 (110/5140). AF 95% confidence interval is 0.0182. There are 2 homozygotes in GnomAd4. There are 61 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006348.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COG5	NM_006348.5	MANE Select	c.1826T>C	p.Ile609Thr	missense	Exon 17 of 22	NP_006339.4
	COG5	NM_181733.4		c.1763T>C	p.Ile588Thr	missense	Exon 16 of 21	NP_859422.3	A0AAA9X096
	COG5	NM_001161520.2		c.1826T>C	p.Ile609Thr	missense	Exon 17 of 21	NP_001154992.2	A0AAA9X2X8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COG5	ENST00000297135.9	TSL:1 MANE Select	c.1826T>C	p.Ile609Thr	missense	Exon 17 of 22	ENSP00000297135.4	Q9UP83-4
	COG5	ENST00000347053.8	TSL:1	c.1763T>C	p.Ile588Thr	missense	Exon 16 of 21	ENSP00000334703.3	A0AAA9X096
	COG5	ENST00000393603.7	TSL:1	c.1826T>C	p.Ile609Thr	missense	Exon 17 of 21	ENSP00000377228.3	A0AAA9X2X8

Frequencies

GnomAD3 genomes AF: 0.000771 AC: 117 AN: 151778 Hom.: 2 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0214

Gnomad SAS AF: 0.000626

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000482

GnomAD2 exomes AF: 0.00189 AC: 474 AN: 251334 AF XY: 0.00174

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0249

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.000431 AC: 629 AN: 1460184 Hom.: 9 Cov.: 30 AF XY: 0.000401 AC XY: 291 AN XY: 726464

African (AFR) AF: 0.00 AC: 0 AN: 33452

American (AMR) AF: 0.0000447 AC: 2 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26114

East Asian (EAS) AF: 0.0131 AC: 521 AN: 39672

South Asian (SAS) AF: 0.000186 AC: 16 AN: 86228

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53290

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5764

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1110610

Other (OTH) AF: 0.00139 AC: 84 AN: 60340

GnomAD4 genome AF: 0.000770 AC: 117 AN: 151904 Hom.: 2 Cov.: 31 AF XY: 0.000822 AC XY: 61 AN XY: 74242

African (AFR) AF: 0.00 AC: 0 AN: 41444

American (AMR) AF: 0.000197 AC: 3 AN: 15226

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3462

East Asian (EAS) AF: 0.0214 AC: 110 AN: 5140

South Asian (SAS) AF: 0.000626 AC: 3 AN: 4792

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10546

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67990

Other (OTH) AF: 0.000477 AC: 1 AN: 2098

Alfa AF: 0.000606 Hom.: 2

Bravo AF: 0.000960

ExAC AF: 0.00177 AC: 215

Asia WGS AF: 0.00606 AC: 21 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	3	COG5-congenital disorder of glycosylation (4)
-	-	2	not specified (2)
-	-	1	COG5-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.34
BayesDel_addAF	Benign	-0.023	T
BayesDel_noAF	Pathogenic	0.22
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.062	T
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D
MetaRNN	Benign	0.011	T
MetaSVM	Benign	-0.89	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		8.1
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-2.6	D
REVEL	Uncertain	0.49
Sift	Uncertain	0.024	D
Sift4G	Uncertain	0.026	D
Polyphen		0.84	P
Vest4		0.98
MVP		0.81
MPC		0.11
ClinPred		0.080	T
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.37
gMVP		0.19
Mutation Taster		=61/39	polymorphism

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: rs142433421; hg19: chr7-106888868;