7-107298208-T-C

Variant names:

• chr7-107298208-T-C
• rs41276187
• NM_006348.5:c.1247A>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.1247A>G​(p.Tyr416Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0062 in 1,613,714 control chromosomes in the GnomAD database, including 43 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 0.0052 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0063 (39 hom.)
• Consequence: COG5 NM_006348.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: -0.583
• Publications: 7 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.003083676).
• BP6: Variant 7-107298208-T-C is Benign according to our data. Variant chr7-107298208-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 194075.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00516 (786/152272) while in subpopulation NFE AF = 0.00798 (543/68014). AF 95% confidence interval is 0.00743. There are 4 homozygotes in GnomAd4. There are 367 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 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.1247A>G	p.Tyr416Cys	missense	Exon 12 of 22	NP_006339.4
	COG5	NM_181733.4		c.1247A>G	p.Tyr416Cys	missense	Exon 12 of 21	NP_859422.3
	COG5	NM_001161520.2		c.1247A>G	p.Tyr416Cys	missense	Exon 12 of 21	NP_001154992.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COG5	ENST00000297135.9	TSL:1 MANE Select	c.1247A>G	p.Tyr416Cys	missense	Exon 12 of 22	ENSP00000297135.4
	COG5	ENST00000347053.8	TSL:1	c.1247A>G	p.Tyr416Cys	missense	Exon 12 of 21	ENSP00000334703.3
	COG5	ENST00000393603.7	TSL:1	c.1247A>G	p.Tyr416Cys	missense	Exon 12 of 21	ENSP00000377228.3

Frequencies

GnomAD3 genomes AF: 0.00517 AC: 786 AN: 152154 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00138

Gnomad AMI AF: 0.0713

Gnomad AMR AF: 0.00471

Gnomad ASJ AF: 0.00576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00113

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00798

Gnomad OTH AF: 0.00574

GnomAD2 exomes AF: 0.00474 AC: 1192 AN: 251284 AF XY: 0.00478

Gnomad AFR exome AF: 0.00111

Gnomad AMR exome AF: 0.00515

Gnomad ASJ exome AF: 0.00506

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00106

Gnomad NFE exome AF: 0.00767

Gnomad OTH exome AF: 0.00572

GnomAD4 exome AF: 0.00631 AC: 9222 AN: 1461442 Hom.: 39 Cov.: 30 AF XY: 0.00620 AC XY: 4509 AN XY: 727048

African (AFR) AF: 0.00105 AC: 35 AN: 33468

American (AMR) AF: 0.00521 AC: 233 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00455 AC: 119 AN: 26126

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39634

South Asian (SAS) AF: 0.000499 AC: 43 AN: 86246

European-Finnish (FIN) AF: 0.00152 AC: 81 AN: 53398

Middle Eastern (MID) AF: 0.00642 AC: 37 AN: 5762

European-Non Finnish (NFE) AF: 0.00749 AC: 8331 AN: 1111716

Other (OTH) AF: 0.00566 AC: 342 AN: 60372

GnomAD4 genome AF: 0.00516 AC: 786 AN: 152272 Hom.: 4 Cov.: 32 AF XY: 0.00493 AC XY: 367 AN XY: 74470

African (AFR) AF: 0.00137 AC: 57 AN: 41560

American (AMR) AF: 0.00471 AC: 72 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00576 AC: 20 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4830

European-Finnish (FIN) AF: 0.00113 AC: 12 AN: 10602

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00798 AC: 543 AN: 68014

Other (OTH) AF: 0.00568 AC: 12 AN: 2114

Alfa AF: 0.00651 Hom.: 12

Bravo AF: 0.00506

TwinsUK AF: 0.00431 AC: 16

ALSPAC AF: 0.00934 AC: 36

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.00512 AC: 44

ExAC AF: 0.00458 AC: 556

Asia WGS AF: 0.000289 AC: 1 AN: 3476

EpiCase AF: 0.00884

EpiControl AF: 0.0107

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.055
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	0.044
DANN	Benign	0.72
DEOGEN2	Benign	0.0066	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.68	T
MetaRNN	Benign	0.0031	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N
PhyloP100		-0.58
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.69	N
REVEL	Benign	0.046
Sift	Benign	0.14	T
Sift4G	Benign	0.18	T
Polyphen		0.0	B
Vest4		0.21
MVP		0.34
MPC		0.065
ClinPred		0.00032	T
GERP RS		-4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.052
gMVP		0.38
Mutation Taster		=100/0	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: rs41276187; hg19: chr7-106938653;