X-116172674-AT-A

Position:

• chrX-116172674-AT-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 4P and 12B. PVS1_Strong BP6_Very_Strong BS2

The NM_000686.5(AGTR2):​c.402del​(p.Phe134LeufsTer5) variant causes a frameshift change. The variant allele was found at a frequency of 0.000575 in 1,208,062 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 211 hemizygotes in GnomAD. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00044 (0 hom., 11 hem., cov: 23)
  • Exomes 𝑓: 0.00059 (0 hom. 200 hem.)
• Consequence: AGTR2 NM_000686.5 frameshift
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts U:1 B:3
• Conservation: PhyloP100: 6.16

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]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.638 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• BP6: Variant X-116172674-AT-A is Benign according to our data. Variant chrX-116172674-AT-A is described in ClinVar as [Likely_benign]. Clinvar id is 11717.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Hemizygotes in GnomAd4 at 11 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AGTR2	NM_000686.5	c.402del	p.Phe134LeufsTer5	frameshift_variant	3/3	ENST00000371906.5
AGTR2	NM_001385624.1	c.402del	p.Phe134LeufsTer5	frameshift_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AGTR2	ENST00000371906.5	c.402del	p.Phe134LeufsTer5	frameshift_variant	3/3	1	NM_000686.5	P1
AGTR2	ENST00000681852.1	c.402del	p.Phe134LeufsTer5	frameshift_variant	2/2			P1
AGTR2	ENST00000680409.1	n.870del		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes AF: 0.000443 AC: 49 AN: 110551 Hom.: 0 Cov.: 23 AF XY: 0.000334 AC XY: 11 AN XY: 32889

Gnomad AFR AF: 0.000132

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000833

Gnomad OTH AF: 0.000668

GnomAD3 exomes AF: 0.000454 AC: 83 AN: 182958 Hom.: 0 AF XY: 0.000414 AC XY: 28 AN XY: 67596

Gnomad AFR exome AF: 0.000228

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000627

Gnomad NFE exome AF: 0.000969

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000589 AC: 646 AN: 1097460 Hom.: 0 Cov.: 31 AF XY: 0.000551 AC XY: 200 AN XY: 362940

Gnomad4 AFR exome AF: 0.0000379

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: 0.000123

Gnomad4 NFE exome AF: 0.000739

Gnomad4 OTH exome AF: 0.000391

GnomAD4 genome AF: 0.000443 AC: 49 AN: 110602 Hom.: 0 Cov.: 23 AF XY: 0.000334 AC XY: 11 AN XY: 32950

Gnomad4 AFR AF: 0.000132

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000833

Gnomad4 OTH AF: 0.000659

Alfa AF: 0.000182 Hom.: 1

Bravo AF: 0.000461

EpiCase AF: 0.000382

EpiControl AF: 0.000593

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1 Benign:1

Uncertain significance, no assertion criteria provided	literature only	OMIM	Aug 08, 2013	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	See Variant Classification Assertion Criteria. -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Jun 01, 2016

- -

AGTR2-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 28, 2019

This variant is classified as likely 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

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: rs387906503; hg19: chrX-115303927;