rs151318611

Positions:

• chr16-69339548-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_032382.5(COG8):​c.5C>T​(p.Ala2Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00114 in 1,608,912 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00085 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (4 hom.)
• Consequence: COG8 NM_032382.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:6
• Conservation: PhyloP100: 1.61

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]

ENSG00000260371 (HGNC:):

NIP7 (HGNC:24328): (nucleolar pre-rRNA processing protein NIP7) Enables RNA binding activity. Predicted to be involved in ribosomal large subunit biogenesis. Located in cytosol; nucleolus; and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.035721958).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000847 (129/152330) while in subpopulation NFE AF= 0.00148 (101/68028). AF 95% confidence interval is 0.00125. There are 0 homozygotes in gnomad4. There are 55 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COG8	NM_032382.5	c.5C>T	p.Ala2Val	missense_variant	1/6	ENST00000306875.10	NP_115758.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COG8	ENST00000306875.10	c.5C>T	p.Ala2Val	missense_variant	1/6	1	NM_032382.5	ENSP00000305459.6
ENSG00000260371	ENST00000563634.1	c.3-2836C>T		intron_variant		4		ENSP00000454500.1
ENSG00000259900	ENST00000564737.1	n.466-2836C>T		intron_variant		5		ENSP00000462747.1

Frequencies

GnomAD3 genomes AF: 0.000848 AC: 129 AN: 152212 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000753

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00148

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.000831 AC: 205 AN: 246564 Hom.: 0 AF XY: 0.000910 AC XY: 122 AN XY: 134136

Gnomad AFR exome AF: 0.000189

Gnomad AMR exome AF: 0.000378

Gnomad ASJ exome AF: 0.000499

Gnomad EAS exome AF: 0.0000550

Gnomad SAS exome AF: 0.0000329

Gnomad FIN exome AF: 0.000930

Gnomad NFE exome AF: 0.00138

Gnomad OTH exome AF: 0.00149

GnomAD4 exome AF: 0.00117 AC: 1705 AN: 1456582 Hom.: 4 Cov.: 32 AF XY: 0.00117 AC XY: 850 AN XY: 724770

Gnomad4 AFR exome AF: 0.000180

Gnomad4 AMR exome AF: 0.000514

Gnomad4 ASJ exome AF: 0.000306

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000813

Gnomad4 FIN exome AF: 0.000896

Gnomad4 NFE exome AF: 0.00141

Gnomad4 OTH exome AF: 0.000731

GnomAD4 genome AF: 0.000847 AC: 129 AN: 152330 Hom.: 0 Cov.: 32 AF XY: 0.000738 AC XY: 55 AN XY: 74490

Gnomad4 AFR AF: 0.000217

Gnomad4 AMR AF: 0.000457

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000753

Gnomad4 NFE AF: 0.00148

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.00132 Hom.: 0

Bravo AF: 0.000703

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.000455 AC: 2

ESP6500EA AF: 0.00116 AC: 10

ExAC AF: 0.000882 AC: 107

EpiCase AF: 0.00115

EpiControl AF: 0.00113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2017	- -
Uncertain significance, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Oct 31, 2016	- -

COG8-congenital disorder of glycosylation Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 02, 2024	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 2 of the COG8 protein (p.Ala2Val). This variant is present in population databases (rs151318611, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with COG8-related conditions. ClinVar contains an entry for this variant (Variation ID: 377233). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.20
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0098	.;T;T
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Benign	0.75	D
LIST_S2	Benign	0.50	T;T;T
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.036	T;T;T
MetaSVM	Benign	-0.84	T
MutationAssessor	Benign	0.69	.;N;.
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	0.010	.;.;N
REVEL	Benign	0.12
Sift	Pathogenic	0.0	.;.;D
Sift4G	Benign	0.070	.;.;T
Polyphen		0.98	D;D;.
Vest4		0.53
MVP		0.65
MPC		0.93
ClinPred		0.074	T
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.25
gMVP		0.62

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

Publications

LitVar

Other links and lift over

dbSNP: rs151318611; hg19: chr16-69373451; COSMIC: COSV54741607; COSMIC: COSV54741607;