rs151129529

Variant names:

• chr7-107248493-G-A
• rs151129529
• NM_006348.5:c.1756C>T

Your query was ambiguous. Multiple possible variants found:

• chr7-107248493-G-A
• chr7-107248493-G-T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BS1_Supporting

The NM_006348.5(COG5):​c.1756C>T​(p.His586Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.000184 in 1,562,248 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00076 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00012 (1 hom.)
• Consequence: COG5 NM_006348.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4 B:1
• Conservation: PhyloP100: 5.81
• Publications: 0 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: ClinGen, G2P, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.011014938).
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000759 (111/146234) while in subpopulation AFR AF = 0.00263 (104/39520). AF 95% confidence interval is 0.00222. There are 0 homozygotes in GnomAd4. There are 39 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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.1756C>T	p.His586Tyr	missense	Exon 17 of 22	NP_006339.4
	COG5	NM_181733.4		c.1693C>T	p.His565Tyr	missense	Exon 16 of 21	NP_859422.3	A0AAA9X096
	COG5	NM_001161520.2		c.1756C>T	p.His586Tyr	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.1756C>T	p.His586Tyr	missense	Exon 17 of 22	ENSP00000297135.4	Q9UP83-4
	COG5	ENST00000347053.8	TSL:1	c.1693C>T	p.His565Tyr	missense	Exon 16 of 21	ENSP00000334703.3	A0AAA9X096
	COG5	ENST00000393603.7	TSL:1	c.1756C>T	p.His586Tyr	missense	Exon 17 of 21	ENSP00000377228.3	A0AAA9X2X8

Frequencies

GnomAD3 genomes AF: 0.000753 AC: 110 AN: 146118 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00261

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000342

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000150

Gnomad OTH AF: 0.000494

GnomAD2 exomes AF: 0.000238 AC: 58 AN: 243846 AF XY: 0.000197

Gnomad AFR exome AF: 0.00215

Gnomad AMR exome AF: 0.000267

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000807

Gnomad OTH exome AF: 0.000337

GnomAD4 exome AF: 0.000124 AC: 176 AN: 1416014 Hom.: 1 Cov.: 27 AF XY: 0.000123 AC XY: 87 AN XY: 706418

African (AFR) AF: 0.00239 AC: 77 AN: 32202

American (AMR) AF: 0.000274 AC: 12 AN: 43854

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25620

East Asian (EAS) AF: 0.00 AC: 0 AN: 39258

South Asian (SAS) AF: 0.000119 AC: 10 AN: 84254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50352

Middle Eastern (MID) AF: 0.00159 AC: 9 AN: 5666

European-Non Finnish (NFE) AF: 0.0000390 AC: 42 AN: 1075960

Other (OTH) AF: 0.000442 AC: 26 AN: 58848

GnomAD4 genome AF: 0.000759 AC: 111 AN: 146234 Hom.: 0 Cov.: 31 AF XY: 0.000550 AC XY: 39 AN XY: 70872

African (AFR) AF: 0.00263 AC: 104 AN: 39520

American (AMR) AF: 0.000342 AC: 5 AN: 14622

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3434

East Asian (EAS) AF: 0.00 AC: 0 AN: 5018

South Asian (SAS) AF: 0.00 AC: 0 AN: 4636

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8912

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.0000150 AC: 1 AN: 66856

Other (OTH) AF: 0.000488 AC: 1 AN: 2048

Alfa AF: 0.000281 Hom.: 0

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000280 AC: 34

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	16
DANN	Benign	0.86
DEOGEN2	Benign	0.0034	T
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.39
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.64	T
M_CAP	Benign	0.0095	T
MetaRNN	Benign	0.011	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L
PhyloP100		5.8
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-0.93	N
REVEL	Benign	0.089
Sift	Benign	0.14	T
Sift4G	Uncertain	0.034	D
Polyphen		0.0030	B
Vest4		0.43
MVP		0.55
MPC		0.061
ClinPred		0.012	T
GERP RS		4.0
Varity_R		0.053
gMVP		0.32
Mutation Taster		=98/2	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: rs151129529; hg19: chr7-106888938; COSMIC: COSV107381628;