chr1-230693233-T-C

Variant names:

• chr1-230693233-T-C
• rs187524214
• NM_007357.3:c.2116-59T>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_007357.3(COG2):​c.2116-59T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00238 in 969,500 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0083 (14 hom., cov: 33)
  • Exomes 𝑓: 0.0013 (4 hom.)
• Consequence: COG2 NM_007357.3 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0150
• Publications: 0 publications found

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]

AGT Gene-Disease associations (from GenCC):

• renal tubular dysgenesis of genetic origin

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

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 1-230693233-T-C is Benign according to our data. Variant chr1-230693233-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 1707266.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00827 (1250/151142) while in subpopulation AFR AF = 0.0251 (1023/40706). AF 95% confidence interval is 0.0239. There are 14 homozygotes in GnomAd4. There are 631 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 14 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_007357.3. 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
	COG2	NM_007357.3	MANE Select	c.2116-59T>C		intron	N/A	NP_031383.1	Q14746-1
	COG2	NM_001145036.2		c.2113-59T>C		intron	N/A	NP_001138508.1	Q14746-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COG2	ENST00000366669.9	TSL:1 MANE Select	c.2116-59T>C		intron	N/A	ENSP00000355629.4	Q14746-1
	COG2	ENST00000366668.7	TSL:1	c.2113-59T>C		intron	N/A	ENSP00000355628.3	Q14746-2
	AGT	ENST00000680783.1		c.*1178A>G		3_prime_UTR	Exon 3 of 3	ENSP00000506329.1	A0A7P0TAP4

Frequencies

GnomAD3 genomes AF: 0.00822 AC: 1242 AN: 151026 Hom.: 14 Cov.: 33

Gnomad AFR AF: 0.0250

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00784

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00562

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.0000945

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000544

Gnomad OTH AF: 0.0125

GnomAD4 exome AF: 0.00129 AC: 1057 AN: 818358 Hom.: 4 AF XY: 0.00120 AC XY: 514 AN XY: 429120

African (AFR) AF: 0.0226 AC: 432 AN: 19086

American (AMR) AF: 0.00348 AC: 129 AN: 37112

Ashkenazi Jewish (ASJ) AF: 0.00152 AC: 32 AN: 21006

East Asian (EAS) AF: 0.00285 AC: 101 AN: 35440

South Asian (SAS) AF: 0.000506 AC: 34 AN: 67210

European-Finnish (FIN) AF: 0.000116 AC: 6 AN: 51908

Middle Eastern (MID) AF: 0.00205 AC: 9 AN: 4398

European-Non Finnish (NFE) AF: 0.000372 AC: 202 AN: 543692

Other (OTH) AF: 0.00291 AC: 112 AN: 38506

GnomAD4 genome AF: 0.00827 AC: 1250 AN: 151142 Hom.: 14 Cov.: 33 AF XY: 0.00854 AC XY: 631 AN XY: 73914

African (AFR) AF: 0.0251 AC: 1023 AN: 40706

American (AMR) AF: 0.00783 AC: 119 AN: 15202

Ashkenazi Jewish (ASJ) AF: 0.00202 AC: 7 AN: 3466

East Asian (EAS) AF: 0.00583 AC: 30 AN: 5150

South Asian (SAS) AF: 0.00105 AC: 5 AN: 4782

European-Finnish (FIN) AF: 0.0000945 AC: 1 AN: 10586

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.000530 AC: 36 AN: 67952

Other (OTH) AF: 0.0124 AC: 26 AN: 2098

Alfa AF: 0.000693 Hom.: 0

Bravo AF: 0.00918

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.27
DANN	Benign	0.42
PhyloP100		0.015
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: rs187524214; hg19: chr1-230828979; COSMIC: COSV64188401; COSMIC: COSV64188401;