NM_000686.5:c.61G>A

Variant names:

• chrX-116172341-G-A
• rs373687647
• NM_000686.5:c.61G>A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_000686.5(AGTR2):​c.61G>A​(p.Gly21Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000091 in 1,208,927 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G21V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000090 (0 hom., 0 hem., cov: 23)
  • Exomes 𝑓: 0.0000091 (0 hom. 3 hem.)
• Consequence: AGTR2 NM_000686.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.455
• Publications: 0 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.10513201).
• BS2: High Hemizygotes in GnomAdExome4 at 3 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AGTR2	NM_000686.5	MANE Select	c.61G>A	p.Gly21Arg	missense	Exon 3 of 3	NP_000677.2
	AGTR2	NM_001385624.1		c.61G>A	p.Gly21Arg	missense	Exon 2 of 2	NP_001372553.1	P50052

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AGTR2	ENST00000371906.5	TSL:1 MANE Select	c.61G>A	p.Gly21Arg	missense	Exon 3 of 3	ENSP00000360973.4	P50052
	AGTR2	ENST00000681852.1		c.61G>A	p.Gly21Arg	missense	Exon 2 of 2	ENSP00000505750.1	P50052
	AGTR2	ENST00000971224.1		c.61G>A	p.Gly21Arg	missense	Exon 3 of 3	ENSP00000641283.1

Frequencies

GnomAD3 genomes AF: 0.00000898 AC: 1 AN: 111334 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00

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: 0.0000188

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000911 AC: 10 AN: 1097540 Hom.: 0 Cov.: 31 AF XY: 0.00000826 AC XY: 3 AN XY: 363076

African (AFR) AF: 0.00 AC: 0 AN: 26371

American (AMR) AF: 0.0000285 AC: 1 AN: 35141

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19359

East Asian (EAS) AF: 0.00 AC: 0 AN: 30195

South Asian (SAS) AF: 0.00 AC: 0 AN: 54133

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40518

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4134

European-Non Finnish (NFE) AF: 0.0000107 AC: 9 AN: 841625

Other (OTH) AF: 0.00 AC: 0 AN: 46064

GnomAD4 genome AF: 0.00000898 AC: 1 AN: 111387 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 33657

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 30642

American (AMR) AF: 0.00 AC: 0 AN: 10473

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2636

East Asian (EAS) AF: 0.00 AC: 0 AN: 3532

South Asian (SAS) AF: 0.00 AC: 0 AN: 2652

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5971

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 219

European-Non Finnish (NFE) AF: 0.0000188 AC: 1 AN: 53060

Other (OTH) AF: 0.00 AC: 0 AN: 1521

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000149 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	6.8
DANN	Benign	0.56
DEOGEN2	Benign	0.24	T
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.44	T
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	N
PhyloP100		0.46
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-0.56	N
REVEL	Benign	0.12
Sift	Benign	0.24	T
Sift4G	Benign	0.28	T
Polyphen		0.0	B
Vest4		0.099
MutPred		0.53		Gain of sheet (P = 0.0507)
MVP		0.87
MPC		0.17
ClinPred		0.051	T
GERP RS		1.8
Varity_R		0.077
gMVP		0.51
Mutation Taster		=93/7	polymorphism

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

Other links and lift over

dbSNP: rs373687647; hg19: chrX-115303594;