rs5191

Variant names:

• chrX-116173023-G-A
• rs5191
• NM_000686.5:c.743G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

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. 13/20 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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.888
• Publications: 6 publications found

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 Gene-Disease associations (from GenCC):

• non-syndromic X-linked intellectual disability

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
• X-linked complex neurodevelopmental disorder

  Inheritance: XL Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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 the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 12 XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000686.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AGTR2	NM_000686.5	MANE Select	c.743G>A	p.Arg248Lys	missense	Exon 3 of 3	NP_000677.2
	AGTR2	NM_001385624.1		c.743G>A	p.Arg248Lys	missense	Exon 2 of 2	NP_001372553.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AGTR2	ENST00000371906.5	TSL:1 MANE Select	c.743G>A	p.Arg248Lys	missense	Exon 3 of 3	ENSP00000360973.4
	AGTR2	ENST00000681852.1		c.743G>A	p.Arg248Lys	missense	Exon 2 of 2	ENSP00000505750.1
	AGTR2	ENST00000680409.1		n.1211G>A		non_coding_transcript_exon	Exon 1 of 1

Frequencies

GnomAD3 genomes AF: 0.0112 AC: 1250 AN: 111636 Hom.: 12 Cov.: 23

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

GnomAD2 exomes AF: 0.00342 AC: 624 AN: 182637 AF XY: 0.00233

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 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.: 21 Cov.: 31 AF XY: 0.00111 AC XY: 403 AN XY: 363432

African (AFR) AF: 0.0446 AC: 1176 AN: 26390

American (AMR) AF: 0.00270 AC: 95 AN: 35174

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19369

East Asian (EAS) AF: 0.00 AC: 0 AN: 30204

South Asian (SAS) AF: 0.000129 AC: 7 AN: 54124

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40524

Middle Eastern (MID) AF: 0.00363 AC: 15 AN: 4134

European-Non Finnish (NFE) AF: 0.0000677 AC: 57 AN: 841982

Other (OTH) AF: 0.00295 AC: 136 AN: 46087

GnomAD4 genome AF: 0.0112 AC: 1251 AN: 111688 Hom.: 12 Cov.: 23 AF XY: 0.0102 AC XY: 346 AN XY: 33894

African (AFR) AF: 0.0384 AC: 1183 AN: 30781

American (AMR) AF: 0.00487 AC: 51 AN: 10462

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2649

East Asian (EAS) AF: 0.00 AC: 0 AN: 3550

South Asian (SAS) AF: 0.00 AC: 0 AN: 2635

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6094

Middle Eastern (MID) AF: 0.00463 AC: 1 AN: 216

European-Non Finnish (NFE) AF: 0.0000753 AC: 4 AN: 53093

Other (OTH) AF: 0.00790 AC: 12 AN: 1519

Alfa AF: 0.00396 Hom.: 181

Bravo AF: 0.0134

ESP6500AA AF: 0.0370 AC: 142

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00365 AC: 443

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	AGTR2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.78	T
BayesDel_noAF	Benign	-0.86
CADD	Benign	15
DANN	Benign	0.61
DEOGEN2	Benign	0.16	T
FATHMM_MKL	Benign	0.40	N
LIST_S2	Benign	0.61	T
MetaRNN	Benign	0.0024	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.10	N
PhyloP100		0.89
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	0.46	N
REVEL	Benign	0.080
Sift	Benign	0.81	T
Sift4G	Benign	1.0	T
Polyphen		0.015	B
Vest4		0.051
MVP		0.64
MPC		0.15
ClinPred		0.0045	T
GERP RS		3.8
Varity_R		0.26
gMVP		0.69
Mutation Taster		=95/5	polymorphism (auto)

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

Other links and lift over

dbSNP: rs5191; hg19: chrX-115304276; COSMIC: COSV64156632;