rs5191

Positions:

chrX-116173023-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000686.5(AGTR2):c.743G>A(p.Arg248Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00226 in 1,209,676 control chromosomes in the GnomAD database, including 33 homozygotes. There are 749 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.011 ( 12 hom., 346 hem., cov: 23)

Exomes 𝑓: 0.0014 ( 21 hom. 403 hem. )

Consequence

AGTR2
NM_000686.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.888

Variant links:

Genes affected

AGTR2 (HGNC:338): (angiotensin II receptor type 2) The protein encoded by this gene belongs to the G-protein coupled receptor 1 family, and functions as a receptor for angiotensin II. It is an intergral membrane protein that is highly expressed in fetus and in neonates, but scantily in adult tissues, except brain, adrenal medulla, and atretic ovary. This receptor has been shown to mediate programmed cell death and this apoptotic function may play an important role in developmental biology and pathophysiology. Mutations in this gene are been associated with X-linked cognitive disability. Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) and SARS-CoV-2 infection results in down-regulation of angiotensin converting enzyme-2 (ACE2) receptors, the effects of which, triggers serious inflammatory lesions in the tissues involved, primarily in the lungs. The inflammatory reaction appears to be mediated by angiotensin II derivatives, including the angiotensin AT2 receptor which has been found to be upregulated in bronchoalveolar lavage samples from Coronavirus disease 2019 (COVID19) patients. [provided by RefSeq, Jul 2020]

AGTR2 links:

AGTR2 (HGNC:):

AGTR2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0024190247).

BP6

Variant X-116173023-G-A is Benign according to our data. Variant chrX-116173023-G-A is described in ClinVar as [Benign]. Clinvar id is 93332.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0112 (1251/111688) while in subpopulation AFR AF= 0.0384 (1183/30781). AF 95% confidence interval is 0.0366. There are 12 homozygotes in gnomad4. There are 346 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 12 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AGTR2	NM_000686.5 linkuse as main transcript	c.743G>A	p.Arg248Lys	missense_variant	3/3	ENST00000371906.5	NP_000677.2	P50052
AGTR2	NM_001385624.1 linkuse as main transcript	c.743G>A	p.Arg248Lys	missense_variant	2/2		NP_001372553.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
AGTR2	ENST00000371906.5 linkuse as main transcript	c.743G>A	p.Arg248Lys	missense_variant	3/3	1	NM_000686.5	ENSP00000360973.4	P50052
AGTR2	ENST00000681852.1 linkuse as main transcript	c.743G>A	p.Arg248Lys	missense_variant	2/2			ENSP00000505750.1	P50052
AGTR2	ENST00000680409.1 linkuse as main transcript	n.1211G>A		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes

AF:

0.0112

AC:

1250

AN:

111636

Hom.:

Cov.:

AF XY:

0.0102

AC XY:

346

AN XY:

33832

show subpopulations

Gnomad AFR

AF:

0.0385

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00488

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000378

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00424

Gnomad NFE

AF:

0.0000753

Gnomad OTH

AF:

0.00801

GnomAD3 exomes

AF:

0.00342

AC:

624

AN:

182637

Hom.:

AF XY:

0.00233

AC XY:

157

AN XY:

67389

show subpopulations

Gnomad AFR exome

AF:

0.0415

Gnomad AMR exome

AF:

0.00245

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000157

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000492

Gnomad OTH exome

AF:

0.000887

GnomAD4 exome

AF:

0.00135

AC:

1486

AN:

1097988

Hom.:

Cov.:

AF XY:

0.00111

AC XY:

403

AN XY:

363432

show subpopulations

Gnomad4 AFR exome

AF:

0.0446

Gnomad4 AMR exome

AF:

0.00270

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000129

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000677

Gnomad4 OTH exome

AF:

0.00295

GnomAD4 genome

AF:

0.0112

AC:

1251

AN:

111688

Hom.:

Cov.:

AF XY:

0.0102

AC XY:

346

AN XY:

33894

show subpopulations

Gnomad4 AFR

AF:

0.0384

Gnomad4 AMR

AF:

0.00487

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000753

Gnomad4 OTH

AF:

0.00790

Alfa

AF:

0.00134

Hom.:

Bravo

AF:

0.0134

ESP6500AA

AF:

0.0370

AC:

142

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00365

AC:

443

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 16, 2015	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 31, 2013	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 20, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

AGTR2-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 08, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.093

BayesDel_addAF

Benign

-0.78

BayesDel_noAF

Benign

-0.86

CADD

Benign

DANN

Benign

0.61

DEOGEN2

Benign

0.16

FATHMM_MKL

Benign

0.40

LIST_S2

Benign

0.61

MetaRNN

Benign

0.0024

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.10

PrimateAI

Uncertain

0.50

PROVEAN

Benign

0.46

REVEL

Benign

0.080

Sift

Benign

0.81

Sift4G

Benign

1.0

Polyphen

0.015

Vest4

0.051

MVP

0.64

MPC

0.15

ClinPred

0.0045

GERP RS

3.8

Varity_R

0.26

gMVP

0.69

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over