rs114861924

Variant names:

• chr16-69331089-G-A
• rs114861924
• NM_032382.5:c.1589C>T

Your query was ambiguous. Multiple possible variants found:

• chr16-69331089-G-A
• chr16-69331089-G-C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_032382.5(COG8):​c.1589C>T​(p.Pro530Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00162 in 1,613,924 control chromosomes in the GnomAD database, including 36 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P530R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0088 (22 hom., cov: 32)
  • Exomes 𝑓: 0.00087 (14 hom.)
• Consequence: COG8 NM_032382.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 5.46
• Publications: 0 publications found

Genes affected

COG8 (HGNC:18623): (component of oligomeric golgi complex 8) This gene encodes a protein that is a component of the conserved oligomeric Golgi (COG) complex, a multiprotein complex that plays a structural role in the Golgi apparatus, and is involved in intracellular membrane trafficking and glycoprotein modification. Mutations in this gene cause congenital disorder of glycosylation, type IIh, a disease that is characterized by under-glycosylated serum proteins, and whose symptoms include severe psychomotor retardation, failure to thrive, seizures, and dairy and wheat product intolerance. [provided by RefSeq, Jul 2008]

COG8 Gene-Disease associations (from GenCC):

• COG8-congenital disorder of glycosylation

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, PanelApp Australia, Orphanet, Labcorp Genetics (formerly Invitae)

ENSG00000272617 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0053434074).
• BP6: Variant 16-69331089-G-A is Benign according to our data. Variant chr16-69331089-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 235266.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00876 (1334/152346) while in subpopulation AFR AF = 0.0297 (1235/41586). AF 95% confidence interval is 0.0283. There are 22 homozygotes in GnomAd4. There are 631 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 22 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032382.5. 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
	COG8	NM_032382.5	MANE Select	c.1589C>T	p.Pro530Leu	missense	Exon 5 of 6	NP_115758.3
	COG8	NM_001379261.1		c.1730C>T	p.Pro577Leu	missense	Exon 6 of 7	NP_001366190.1
	COG8	NM_001379262.1		c.1589C>T	p.Pro530Leu	missense	Exon 5 of 6	NP_001366191.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COG8	ENST00000306875.10	TSL:1 MANE Select	c.1589C>T	p.Pro530Leu	missense	Exon 5 of 6	ENSP00000305459.6
	ENSG00000272617	ENST00000562949.1	TSL:3	c.352-1910C>T		intron	N/A	ENSP00000457718.1
	COG8	ENST00000562595.5	TSL:5	c.548+4237C>T		intron	N/A	ENSP00000456705.1

Frequencies

GnomAD3 genomes AF: 0.00877 AC: 1335 AN: 152228 Hom.: 22 Cov.: 32

Gnomad AFR AF: 0.0298

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00445

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.00862

GnomAD2 exomes AF: 0.00221 AC: 551 AN: 249382 AF XY: 0.00147

Gnomad AFR exome AF: 0.0297

Gnomad AMR exome AF: 0.00142

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000161

Gnomad OTH exome AF: 0.000818

GnomAD4 exome AF: 0.000872 AC: 1274 AN: 1461578 Hom.: 14 Cov.: 32 AF XY: 0.000755 AC XY: 549 AN XY: 727068

African (AFR) AF: 0.0294 AC: 984 AN: 33472

American (AMR) AF: 0.00161 AC: 72 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.000104 AC: 9 AN: 86238

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53260

Middle Eastern (MID) AF: 0.000693 AC: 4 AN: 5768

European-Non Finnish (NFE) AF: 0.0000764 AC: 85 AN: 1111940

Other (OTH) AF: 0.00199 AC: 120 AN: 60380

GnomAD4 genome AF: 0.00876 AC: 1334 AN: 152346 Hom.: 22 Cov.: 32 AF XY: 0.00847 AC XY: 631 AN XY: 74502

African (AFR) AF: 0.0297 AC: 1235 AN: 41586

American (AMR) AF: 0.00444 AC: 68 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000176 AC: 12 AN: 68036

Other (OTH) AF: 0.00853 AC: 18 AN: 2110

Alfa AF: 0.00401 Hom.: 20

Bravo AF: 0.00968

ESP6500AA AF: 0.0284 AC: 125

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00284 AC: 345

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000237

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	COG8-congenital disorder of glycosylation (3)
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.38
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.052	T
Eigen	Benign	0.14
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.84	T
MetaRNN	Benign	0.0053	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		5.5
PrimateAI	Benign	0.46	T
PROVEAN	Pathogenic	-6.3	D
REVEL	Benign	0.13
Sift	Uncertain	0.0010	D
Polyphen		0.012	B
MVP		0.55
MPC		0.15
ClinPred		0.049	T
GERP RS		5.5
Varity_R		0.23
gMVP		0.55
Mutation Taster		=89/11	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs114861924; hg19: chr16-69364992;