7-107298193-T-C

Variant names:

• chr7-107298193-T-C
• rs35393416
• NM_006348.5:c.1262A>G

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.1262A>G​(p.His421Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00383 in 1,613,208 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0028 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0039 (21 hom.)
• Consequence: COG5 NM_006348.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 1.86
• Publications: 12 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: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0037671328).
• BP6: Variant 7-107298193-T-C is Benign according to our data. Variant chr7-107298193-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 358461.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00281 (428/152302) while in subpopulation NFE AF = 0.00463 (315/68006). AF 95% confidence interval is 0.00421. There are 0 homozygotes in GnomAd4. There are 196 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 21 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.1262A>G	p.His421Arg	missense	Exon 12 of 22	NP_006339.4
	COG5	NM_181733.4		c.1262A>G	p.His421Arg	missense	Exon 12 of 21	NP_859422.3	A0AAA9X096
	COG5	NM_001161520.2		c.1262A>G	p.His421Arg	missense	Exon 12 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.1262A>G	p.His421Arg	missense	Exon 12 of 22	ENSP00000297135.4	Q9UP83-4
	COG5	ENST00000347053.8	TSL:1	c.1262A>G	p.His421Arg	missense	Exon 12 of 21	ENSP00000334703.3	A0AAA9X096
	COG5	ENST00000393603.7	TSL:1	c.1262A>G	p.His421Arg	missense	Exon 12 of 21	ENSP00000377228.3	A0AAA9X2X8

Frequencies

GnomAD3 genomes AF: 0.00281 AC: 427 AN: 152184 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000579

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00268

Gnomad ASJ AF: 0.00374

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00414

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00462

Gnomad OTH AF: 0.00383

GnomAD2 exomes AF: 0.00347 AC: 873 AN: 251248 AF XY: 0.00389

Gnomad AFR exome AF: 0.000677

Gnomad AMR exome AF: 0.00243

Gnomad ASJ exome AF: 0.00298

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000832

Gnomad NFE exome AF: 0.00492

Gnomad OTH exome AF: 0.00555

GnomAD4 exome AF: 0.00394 AC: 5758 AN: 1460906 Hom.: 21 Cov.: 30 AF XY: 0.00410 AC XY: 2978 AN XY: 726736

African (AFR) AF: 0.000478 AC: 16 AN: 33450

American (AMR) AF: 0.00244 AC: 109 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00310 AC: 81 AN: 26098

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39620

South Asian (SAS) AF: 0.00488 AC: 420 AN: 86122

European-Finnish (FIN) AF: 0.00137 AC: 73 AN: 53360

Middle Eastern (MID) AF: 0.0184 AC: 106 AN: 5754

European-Non Finnish (NFE) AF: 0.00419 AC: 4660 AN: 1111442

Other (OTH) AF: 0.00484 AC: 292 AN: 60348

GnomAD4 genome AF: 0.00281 AC: 428 AN: 152302 Hom.: 0 Cov.: 32 AF XY: 0.00263 AC XY: 196 AN XY: 74482

African (AFR) AF: 0.000577 AC: 24 AN: 41584

American (AMR) AF: 0.00268 AC: 41 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00374 AC: 13 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00415 AC: 20 AN: 4824

European-Finnish (FIN) AF: 0.000377 AC: 4 AN: 10604

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

European-Non Finnish (NFE) AF: 0.00463 AC: 315 AN: 68006

Other (OTH) AF: 0.00379 AC: 8 AN: 2110

Alfa AF: 0.00394 Hom.: 8

Bravo AF: 0.00296

TwinsUK AF: 0.00297 AC: 11

ALSPAC AF: 0.00467 AC: 18

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00430 AC: 37

ExAC AF: 0.00344 AC: 417

Asia WGS AF: 0.000867 AC: 3 AN: 3476

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	13
DANN	Benign	0.66
DEOGEN2	Benign	0.0043	T
Eigen	Benign	-0.79
Eigen_PC	Benign	-0.70
FATHMM_MKL	Benign	0.44	N
LIST_S2	Benign	0.63	T
MetaRNN	Benign	0.0038	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.90	L
PhyloP100		1.9
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.68	N
REVEL	Benign	0.043
Sift	Benign	0.34	T
Sift4G	Benign	0.37	T
Polyphen		0.0060	B
Vest4		0.31
MVP		0.53
MPC		0.064
ClinPred		0.0048	T
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.043
gMVP		0.28
Mutation Taster		=99/1	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: rs35393416; hg19: chr7-106938638; COSMIC: COSV99773705;