chr1-230691841-A-G

Variant names:

• chr1-230691841-A-G
• rs41271497
• NM_007357.3:c.2115+277A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_007357.3(COG2):​c.2115+277A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0304 in 346,408 control chromosomes in the GnomAD database, including 228 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.025 (70 hom., cov: 32)
  • Exomes 𝑓: 0.035 (158 hom.)
• Consequence: COG2 NM_007357.3 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.950
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 1-230691841-A-G is Benign according to our data. Variant chr1-230691841-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 1318104.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0651 is higher than 0.05.

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.2115+277A>G		intron	N/A	NP_031383.1	Q14746-1
	COG2	NM_001145036.2		c.2112+277A>G		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.2115+277A>G		intron	N/A	ENSP00000355629.4	Q14746-1
	COG2	ENST00000366668.7	TSL:1	c.2112+277A>G		intron	N/A	ENSP00000355628.3	Q14746-2
	AGT	ENST00000680783.1		c.*2570T>C		3_prime_UTR	Exon 3 of 3	ENSP00000506329.1	A0A7P0TAP4

Frequencies

GnomAD3 genomes AF: 0.0246 AC: 3744 AN: 152078 Hom.: 70 Cov.: 32

Gnomad AFR AF: 0.00683

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0217

Gnomad ASJ AF: 0.0565

Gnomad EAS AF: 0.000581

Gnomad SAS AF: 0.0710

Gnomad FIN AF: 0.0207

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0337

Gnomad OTH AF: 0.0301

GnomAD4 exome AF: 0.0350 AC: 6804 AN: 194212 Hom.: 158 Cov.: 0 AF XY: 0.0368 AC XY: 3662 AN XY: 99632

African (AFR) AF: 0.00515 AC: 35 AN: 6802

American (AMR) AF: 0.0235 AC: 174 AN: 7402

Ashkenazi Jewish (ASJ) AF: 0.0528 AC: 366 AN: 6934

East Asian (EAS) AF: 0.000212 AC: 3 AN: 14174

South Asian (SAS) AF: 0.0785 AC: 1015 AN: 12936

European-Finnish (FIN) AF: 0.0275 AC: 294 AN: 10684

Middle Eastern (MID) AF: 0.0488 AC: 44 AN: 902

European-Non Finnish (NFE) AF: 0.0362 AC: 4419 AN: 121994

Other (OTH) AF: 0.0367 AC: 454 AN: 12384

GnomAD4 genome AF: 0.0246 AC: 3743 AN: 152196 Hom.: 70 Cov.: 32 AF XY: 0.0244 AC XY: 1812 AN XY: 74402

African (AFR) AF: 0.00681 AC: 283 AN: 41530

American (AMR) AF: 0.0216 AC: 331 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0565 AC: 196 AN: 3470

East Asian (EAS) AF: 0.000582 AC: 3 AN: 5154

South Asian (SAS) AF: 0.0713 AC: 343 AN: 4812

European-Finnish (FIN) AF: 0.0207 AC: 219 AN: 10600

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.0337 AC: 2294 AN: 68010

Other (OTH) AF: 0.0298 AC: 63 AN: 2114

Alfa AF: 0.0287 Hom.: 8

Bravo AF: 0.0230

Asia WGS AF: 0.0270 AC: 95 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.36
DANN	Benign	0.35
PhyloP100		-0.95
Mutation Taster		=100/0	polymorphism (auto)

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: rs41271497; hg19: chr1-230827587;