X-116172342-G-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Moderate BP6_Very_Strong BS2

The NM_000686.5(AGTR2):c.62G>T(p.Gly21Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00403 in 1,208,856 control chromosomes in the GnomAD database, including 13 homozygotes. There are 1,581 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G21R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0027 (2 hom., 76 hem., cov: 23)
  • Exomes 𝑓: 0.0042 (11 hom. 1505 hem.)
• Consequence: AGTR2 NM_000686.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:5
• Conservation: PhyloP100: 0.485

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0701001).
• BP6: Variant X-116172342-G-T is Benign according to our data. Variant chrX-116172342-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 11716.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-116172342-G-T is described in Lovd as [Likely_benign]. Variant chrX-116172342-G-T is described in Lovd as [Benign].
• BS2: High Homozygotes in GnomAd at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AGTR2	NM_000686.5	c.62G>T	p.Gly21Val	missense_variant	3/3	ENST00000371906.5
AGTR2	NM_001385624.1	c.62G>T	p.Gly21Val	missense_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AGTR2	ENST00000371906.5	c.62G>T	p.Gly21Val	missense_variant	3/3	1	NM_000686.5	P1
AGTR2	ENST00000681852.1	c.62G>T	p.Gly21Val	missense_variant	2/2			P1
AGTR2	ENST00000680409.1	n.530G>T		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes AF: 0.00273 AC: 304 AN: 111214 Hom.: 2 Cov.: 23 AF XY: 0.00233 AC XY: 78 AN XY: 33490

Gnomad AFR AF: 0.000426

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00335

Gnomad ASJ AF: 0.00114

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00188

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00837

Gnomad NFE AF: 0.00453

Gnomad OTH AF: 0.00401

GnomAD3 exomes AF: 0.00251 AC: 459 AN: 183135 Hom.: 4 AF XY: 0.00253 AC XY: 171 AN XY: 67693

Gnomad AFR exome AF: 0.000532

Gnomad AMR exome AF: 0.00256

Gnomad ASJ exome AF: 0.00147

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00152

Gnomad FIN exome AF: 0.0000625

Gnomad NFE exome AF: 0.00410

Gnomad OTH exome AF: 0.00133

GnomAD4 exome AF: 0.00417 AC: 4576 AN: 1097590 Hom.: 11 Cov.: 31 AF XY: 0.00414 AC XY: 1505 AN XY: 363134

Gnomad4 AFR exome AF: 0.000531

Gnomad4 AMR exome AF: 0.00256

Gnomad4 ASJ exome AF: 0.000878

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00170

Gnomad4 FIN exome AF: 0.000123

Gnomad4 NFE exome AF: 0.00490

Gnomad4 OTH exome AF: 0.00417

GnomAD4 genome AF: 0.00271 AC: 301 AN: 111266 Hom.: 2 Cov.: 23 AF XY: 0.00227 AC XY: 76 AN XY: 33552

Gnomad4 AFR AF: 0.000425

Gnomad4 AMR AF: 0.00335

Gnomad4 ASJ AF: 0.00114

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00113

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00453

Gnomad4 OTH AF: 0.00330

Alfa AF: 0.00422 Hom.: 175

Bravo AF: 0.00291

TwinsUK AF: 0.00485 AC: 18

ALSPAC AF: 0.00588 AC: 17

ESP6500AA AF: 0.000522 AC: 2

ESP6500EA AF: 0.00461 AC: 31

ExAC AF: 0.00249 AC: 302

EpiCase AF: 0.00551

EpiControl AF: 0.00582

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1 Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 11, 2015	This alteration is classified as likely 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	Genetic Services Laboratory, University of Chicago	Jul 15, 2013	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not provided Uncertain:1 Benign:1

Uncertain significance, no assertion criteria provided	literature only	OMIM	Aug 08, 2013	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Intellectual disability, X-linked 88 Benign:1

Likely benign, no assertion criteria provided

clinical testing

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Uncertain	-0.050
Cadd	Benign	1.7
Dann	Benign	0.44
DEOGEN2	Benign	0.36	T
FATHMM_MKL	Benign	0.093	N
LIST_S2	Benign	0.37	T
M_CAP	Benign	0.035	D
MetaRNN	Benign	0.070	T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	0.34	N
MutationTaster	Benign	0.000013	A
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-0.35	N
REVEL	Uncertain	0.37
Sift	Benign	0.20	T
Sift4G	Benign	0.22	T
Polyphen		0.0	B
Vest4		0.055
MVP		0.85
MPC		0.18
ClinPred		0.0015	T
GERP RS		3.6
Varity_R		0.062
gMVP		0.48

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: rs121917810; hg19: chrX-115303595;