X-116173251-G-C

Variant names:

• chrX-116173251-G-C
• rs35474657
• NM_000686.5:c.971G>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_000686.5(AGTR2):​c.971G>C​(p.Arg324Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000000911 in 1,097,950 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R324Q) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: AGTR2 NM_000686.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.59
• 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.971G>C	p.Arg324Pro	missense	Exon 3 of 3	NP_000677.2
	AGTR2	NM_001385624.1		c.971G>C	p.Arg324Pro	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.971G>C	p.Arg324Pro	missense	Exon 3 of 3	ENSP00000360973.4
	AGTR2	ENST00000681852.1		c.971G>C	p.Arg324Pro	missense	Exon 2 of 2	ENSP00000505750.1
	AGTR2	ENST00000680409.1		n.1439G>C		non_coding_transcript_exon	Exon 1 of 1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 9.11e-7 AC: 1 AN: 1097950 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 363422

African (AFR) AF: 0.00 AC: 0 AN: 26378

American (AMR) AF: 0.00 AC: 0 AN: 35186

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19368

East Asian (EAS) AF: 0.00 AC: 0 AN: 30203

South Asian (SAS) AF: 0.00 AC: 0 AN: 54132

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40532

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4137

European-Non Finnish (NFE) AF: 0.00000119 AC: 1 AN: 841927

Other (OTH) AF: 0.00 AC: 0 AN: 46087

GnomAD4 genome Cov.: 22

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Uncertain	0.074	D
BayesDel_noAF	Benign	-0.13
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.66	D
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.012	T
MetaRNN	Uncertain	0.62	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N
PhyloP100		4.6
PrimateAI	Benign	0.39	T
PROVEAN	Uncertain	-2.6	D
REVEL	Benign	0.28
Sift	Benign	0.056	T
Sift4G	Uncertain	0.037	D
Polyphen		0.86	P
Vest4		0.52
MutPred		0.69		Loss of MoRF binding (P = 0.0049)
MVP		0.95
MPC		0.24
ClinPred		0.93	D
GERP RS		1.7
Varity_R		0.96
gMVP		0.82
Mutation Taster		=54/46	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: rs35474657; hg19: chrX-115304504;