16-69339259-C-A

Variant names:

• chr16-69339259-C-A
• rs1251237362
• NM_032382.5:c.294G>T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_032382.5(COG8):​c.294G>T​(p.Glu98Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000192 in 1,460,294 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000019 (0 hom.)
• Consequence: COG8 NM_032382.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.46

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3549907).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COG8	NM_032382.5	c.294G>T	p.Glu98Asp	missense_variant	Exon 1 of 6	ENST00000306875.10	NP_115758.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COG8	ENST00000306875.10	c.294G>T	p.Glu98Asp	missense_variant	Exon 1 of 6	1	NM_032382.5	ENSP00000305459.6
ENSG00000260371	ENST00000563634.1	c.3-2547G>T		intron_variant	Intron 1 of 2	4		ENSP00000454500.1
ENSG00000259900	ENST00000564737.1	n.466-2547G>T		intron_variant	Intron 3 of 4	5		ENSP00000462747.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.0000192 AC: 28 AN: 1460294 Hom.: 0 Cov.: 31 AF XY: 0.0000193 AC XY: 14 AN XY: 726484

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000243

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Jan 21, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.294G>T (p.E98D) alteration is located in exon 1 (coding exon 1) of the COG8 gene. This alteration results from a G to T substitution at nucleotide position 294, causing the glutamic acid (E) at amino acid position 98 to be replaced by an aspartic acid (D). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.033	.;T;T
Eigen	Benign	0.14
Eigen_PC	Benign	0.20
FATHMM_MKL	Benign	0.56	D
LIST_S2	Benign	0.69	T;T;T
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.35	T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.9	.;L;.
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-1.5	.;.;N
REVEL	Benign	0.12
Sift	Uncertain	0.026	.;.;D
Sift4G	Benign	0.24	.;.;T
Polyphen		0.77	P;P;.
Vest4		0.42
MutPred		0.47		.;Loss of catalytic residue at E98 (P = 0.1468);Loss of catalytic residue at E98 (P = 0.1468);
MVP		0.56
MPC		0.78
ClinPred		0.93	D
GERP RS		4.3
Varity_R		0.43
gMVP		0.37

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: rs1251237362; hg19: chr16-69373162;