rs35474657

chrX-116173251-G-AchrX-116173251-G-C

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_000686.5(AGTR2):c.971G>A(p.Arg324Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000373 in 1,209,444 control chromosomes in the GnomAD database, including 1 homozygotes. There are 115 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 (★).

• Frequency:
  • Genomes: 𝑓 0.0022 (1 hom., 58 hem., cov: 22)
  • Exomes 𝑓: 0.00019 (0 hom. 57 hem.)
• Consequence: AGTR2 NM_000686.5 missense
• Clinical Significance: Likely benign criteria provided, single submitter U:1 B:1
• Conservation: PhyloP100: 4.59

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.05501291).
• BP6: Variant X-116173251-G-A is Benign according to our data. Variant chrX-116173251-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 11718.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Hemizygotes in GnomAd at 56 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AGTR2	NM_000686.5	c.971G>A	p.Arg324Gln	missense_variant	3/3	ENST00000371906.5
AGTR2	NM_001385624.1	c.971G>A	p.Arg324Gln	missense_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AGTR2	ENST00000371906.5	c.971G>A	p.Arg324Gln	missense_variant	3/3	1	NM_000686.5	P1
AGTR2	ENST00000681852.1	c.971G>A	p.Arg324Gln	missense_variant	2/2			P1
AGTR2	ENST00000680409.1	n.1439G>A		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes AF: 0.00214 AC: 238 AN: 111443 Hom.: 1 Cov.: 22 AF XY: 0.00166 AC XY: 56 AN XY: 33669

Gnomad AFR AF: 0.00748

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000385

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: 0.0000377

Gnomad OTH AF: 0.00203

GnomAD3 exomes AF: 0.000552 AC: 101 AN: 183068 Hom.: 0 AF XY: 0.000384 AC XY: 26 AN XY: 67660

Gnomad AFR exome AF: 0.00722

Gnomad AMR exome AF: 0.000110

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000123

Gnomad OTH exome AF: 0.000443

GnomAD4 exome AF: 0.000192 AC: 211 AN: 1097949 Hom.: 0 Cov.: 31 AF XY: 0.000157 AC XY: 57 AN XY: 363421

Gnomad4 AFR exome AF: 0.00713

Gnomad4 AMR exome AF: 0.000142

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000185

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000713

Gnomad4 OTH exome AF: 0.000239

GnomAD4 genome AF: 0.00215 AC: 240 AN: 111495 Hom.: 1 Cov.: 22 AF XY: 0.00172 AC XY: 58 AN XY: 33731

Gnomad4 AFR AF: 0.00752

Gnomad4 AMR AF: 0.000384

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000377

Gnomad4 OTH AF: 0.00200

Alfa AF: 0.000138 Hom.: 2

Bravo AF: 0.00216

ESP6500AA AF: 0.00730 AC: 28

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000692 AC: 84

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

OMIM

Aug 08, 2013

- -

AGTR2-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 23, 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

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.76
Cadd	Benign	16
Dann	Benign	0.76
DEOGEN2	Benign	0.17	T
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.0024	T
MetaRNN	Benign	0.055	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
MutationTaster	Benign	0.0060	A
PrimateAI	Benign	0.34	T
PROVEAN	Benign	0.0	N
REVEL	Benign	0.086
Sift	Benign	0.83	T
Sift4G	Benign	0.68	T
Polyphen		0.012	B
Vest4		0.082
MVP		0.82
MPC		0.16
ClinPred		0.016	T
GERP RS		1.7
Varity_R		0.19
gMVP		0.24

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs35474657; hg19: chrX-115304504;