1-230691559-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 2P and 10B. PM2 BP4_Strong BP6_Moderate BS1

The NM_007357.3(COG2):c.2110G>A(p.Glu704Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000228 in 1,610,224 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 Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00023 (0 hom.)
• Consequence: COG2 NM_007357.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 5.52

Genes affected

COG2 (HGNC:6546): (component of oligomeric golgi complex 2) This gene encodes a subunit of the conserved oligomeric Golgi complex that is required for maintaining normal structure and activity of the Golgi complex. The encoded protein specifically interacts with the USO1 vesicle docking protein and may be necessary for normal Golgi ribbon formation and trafficking of Golgi enzymes. Mutations of this gene are associated with abnormal glycosylation within the Golgi apparatus. Alternative splicing results in multiple transcript variants.[provided by RefSeq, Feb 2009]

AGT (HGNC:333): (angiotensinogen) The protein encoded by this gene, pre-angiotensinogen or angiotensinogen precursor, is expressed in the liver and is cleaved by the enzyme renin in response to lowered blood pressure. The resulting product, angiotensin I, is then cleaved by angiotensin converting enzyme (ACE) to generate the physiologically active enzyme angiotensin II. The protein is involved in maintaining blood pressure, body fluid and electrolyte homeostasis, and in the pathogenesis of essential hypertension and preeclampsia. Mutations in this gene are associated with susceptibility to essential hypertension, and can cause renal tubular dysgenesis, a severe disorder of renal tubular development. Defects in this gene have also been associated with non-familial structural atrial fibrillation, and inflammatory bowel disease. [provided by RefSeq, Nov 2019]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.057067335).
• BP6: Variant 1-230691559-G-A is Benign according to our data. Variant chr1-230691559-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 752608.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000177 (27/152216) while in subpopulation NFE AF= 0.000309 (21/68040). AF 95% confidence interval is 0.000207. There are 0 homozygotes in gnomad4. There are 13 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COG2	NM_007357.3	c.2110G>A	p.Glu704Lys	missense_variant	17/18	ENST00000366669.9
COG2	NM_001145036.2	c.2107G>A	p.Glu703Lys	missense_variant	17/18
COG2	XM_047449445.1	c.1771G>A	p.Glu591Lys	missense_variant	15/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COG2	ENST00000366669.9	c.2110G>A	p.Glu704Lys	missense_variant	17/18	1	NM_007357.3	P4

Frequencies

GnomAD3 genomes AF: 0.000177 AC: 27 AN: 152216 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000309

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000243 AC: 60 AN: 246974 Hom.: 0 AF XY: 0.000210 AC XY: 28 AN XY: 133614

Gnomad AFR exome AF: 0.0000617

Gnomad AMR exome AF: 0.0000592

Gnomad ASJ exome AF: 0.00252

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000215

Gnomad OTH exome AF: 0.00132

GnomAD4 exome AF: 0.000233 AC: 340 AN: 1458008 Hom.: 0 Cov.: 30 AF XY: 0.000237 AC XY: 172 AN XY: 725100

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000681

Gnomad4 ASJ exome AF: 0.00292

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000218

Gnomad4 OTH exome AF: 0.000316

GnomAD4 genome AF: 0.000177 AC: 27 AN: 152216 Hom.: 0 Cov.: 32 AF XY: 0.000175 AC XY: 13 AN XY: 74360

Gnomad4 AFR AF: 0.0000482

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000309

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.000353 Hom.: 0

Bravo AF: 0.000196

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000148 AC: 18

EpiCase AF: 0.000711

EpiControl AF: 0.000356

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Congenital disorder of glycosylation, type IIq Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 24, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.098	T;.;T
Eigen	Benign	0.051
Eigen_PC	Benign	0.17
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.96	D;D;D
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.057	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	L;.;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.89	N;N;N
REVEL	Benign	0.091
Sift	Benign	0.26	T;T;T
Sift4G	Benign	0.46	T;T;T
Polyphen		0.015	B;.;.
Vest4		0.51
MVP		0.20
MPC		0.17
ClinPred		0.052	T
GERP RS		5.6
Varity_R		0.29
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: rs140155560; hg19: chr1-230827305; COSMIC: COSV64186706; COSMIC: COSV64186706;